Induced Expression of Brain Derived Neurotrophic Factor (BDNF) for Treatment of Neuromuscular, Neurodegenerative, Autoimmune, Developmental and/or Metabolic Diseases

ABSTRACT

A method of treating a host of neuromuscular, neurodegenerative, developmental, autoimmune and metabolic diseases/disorders related to aging, such as traumatic injury, stroke, Huntington&#39;s disease, Epilepsy, Multiple Sclerosis (MS), Lupus, Type-1 and Type-2 diabetes, Maturity Onset Diabetes of the Young (MODY), myasthenia gravis (MG), rheumatoid arthritis (RA), Graves&#39; disease, Guillain-Barré syndrome (GBS), metabolic syndrome, Muscular Dystrophy or Duchenne Muscular Dystrophy (DMD), severe burns, aging, Amyotrophic Lateral Sclerosis (ALS), Friedreich&#39;s Ataxia, Batten Disease, Alzheimer&#39;s disease, optic neuritis, Leber&#39;s hereditary optic neuropathy (LHON), autism, Rett syndrome, Batten Disease, Angelman&#39;s Syndrome, Leigh disease, Fragile-X Syndrome, depression, Parkinson&#39;s disease, mitochondrial diseases, developmental disorders, metabolic disease disorders and/or autoimmune disorders by inducing endogenous BDNF expression with DNP treatment to protect from neuromuscular dysfunction/disorders and/or neurodegeneration and/or muscle wasting. DNP was administered to mice daily over a range of doses, and subsequently BDNF expression in the brain showed a dose dependent and non-linear increase in expression.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims priority to U.S. Provisional Application62/106,365, filed on Jan. 22, 2015, which is expressly incorporatedherein by reference in its entirety.

BACKGROUND OF THE INVENTION

Brain-derived neurotrophic factor (BDNF) is one of several endogenousproteins that play key roles in neuronal development. BDNF influencesnerve growth as a neurotrophin and/or as a myokine. Therefore there is aneed for improved methods for inducing expression of BDNF. The presentinvention relates to the discovery that BDNF can be endogenously inducedto increase expression by administration of DNP, and that there is adose range between 0.001 mg/kg to less than 10 mg/kg that is useful inexpression of BDNF and not harmful to the patient. Further, manyapproaches are underway to get BDNF across the blood brain barrier totreat a host of diseases. For example, these diseases include, but arenot limited to, traumatic injury, stroke, Huntington's disease,Epilepsy, Multiple Sclerosis (MS), Lupus, Type-1 and Type-2 diabetes,Maturity Onset Diabetes of the Young (MODY), Myasthenia gravis (MG),rheumatoid arthritis (RA), Graves' disease, Guillain-Barré syndrome(GBS), metabolic syndrome, Duchenne Muscular Dystrophy (DMD), severeburns, aging, Amyotrophic Lateral Sclerosis (ALS), Friedreich's Ataxia,Batten Disease, Alzheimer's disease, Optic neuritis, Leber's hereditaryoptic neuropathy (LHON), Autism, Rett syndrome, Batten Disease,Angelman's Syndrome, Leigh disease, Fragile-X Syndrome, Schizophrenia,Depression, Parkinson's disease and mitochondrial diseases. Treatmentworks by the process of reversing, slowing or preventing neuromuscular,neurodegenerative, autoimmune, developmental and/or metabolic disorders.

FIELD OF THE INVENTION

The present invention relates to methods of treatment of neuromuscular,neurodegenerative, autoimmune, developmental and/or metabolic diseaseand pharmaceutical compositions, including unit doses, for treatment ofneuromuscular, neurodegenerative, autoimmune, developmental and/ormetabolic disease. Specifically, the present invention relates toendogenously inducing the systemic organs of a person to increaseexpression of brain derived neurotrophin factor (“BDNF”) viaadministering mitochondrial uncoupler (protonophore or ionophore)2,4-dinitrophenol (“DNP”) or bipartite dinitrophenol isoforms (2,3-,2,4-, 2,5-, 2,6-, 3,4-, or 3,5-DNP) or mitochondrial uncouplers or weakacid's with a dissociable proton such as CCCP, FCCP, SF 6847, Flufenamicacid, PCP, TTFB, etc., to a patient in need thereof, using an effectivedose of about 0.001 mg/kg to 5 mg/kg, as well as the associatedpharmaceutical composition of DNP and unit dose of DNP.

BRIEF SUMMARY OF THE INVENTION

In one embodiment, the present invention provides for a method oftreating traumatic CNS injury, neurodegenerative disease, and/orautoimmune diseases, and/or developmental disorders, and/or metabolicdisease by administrating DNP in the dose range of 0.01 mg/kg of bodyweight to less than 10 mg/kg of body weight to increase BDNF toattenuate disease progression or provide relief from symptoms. Incertain embodiments, the invention provides a method of treatment for atleast the following diseases: Traumatic Brain Injury (TBI), Ischemicstroke, Huntington's disease (Adult-onset Huntington's, JuvenileHuntington's disease), Epilepsy (Cluster Seizures, Refractory Seizures,Atypical Absence Seizures, Atonic Seizures, Clonic Seizures, myoclonicseizures, tonic seizures, Tonic-Clonic Seizures, Simple PartialSeizures, Complex Partial Seizures, Secondary Generalized Seizures,Febrile Seizures, Nonepileptic Seizures, Gelastic and DacrysticSeizures, and Absence Seizures), Multiple Sclerosis (MS)(relapse-remitting multiple sclerosis (RRMS), Secondary-progressive MS(SPMS), Primary-progressive MS (PPMS), and Progressive-relapsing MS(PRMS)), Lupus (Systemic Lupus Erythematosus (SLE), discoid (cutaneous),drug-induced lupus (dil) and neonatal lupus), Diabetes mellitus (Type-1Diabetes, Type-2 Diabetes, Maturity Onset Diabetes of the Young (MODY:MODY1, MODY2, MODY3, MODY4, MODY5, MODY6, MODY7, MODY8, MODY9, MODY10,MODY11)), Schizophrenia (Paranoid schizophrenia, Disorganizedschizophrenia, Catatonic schizophrenia, Residual schizophrenia,Schizoaffective disorder), Myasthenia gravis (MG) (ocular myastheniagravis, Congenital MG and generalized myasthenia gravis), rheumatoidarthritis (RA), Graves' disease, Guillain-Barré syndrome (GBS), MuscularDystrophy (Duchenne Muscular Dystrophy (DMD), Becker, Myotonic,Congenital, Emery-Dreifuss, Facioscapulohumeral, Limb-girdle, Distal,and Oculopharyngeal), severe burns, aging, Amyotrophic Lateral Sclerosis(ALS), Ataxia (Friedreich's Ataxia, Spinocerebellar ataxias 1 (SCA1),Spinocerebellar ataxias 2 (SCA2), Spinocerebellar ataxias 3 (SCA3),Spinocerebellar ataxias 6 (SCA6), Spinocerebellar ataxias 7 (SCAT),Spinocerebellar ataxias 11 (SCA11), Dentatorubral pallidolusyian atrophy(DRPLA) and Gluten ataxia), Batten Disease or neuronal ceroidlipofuscinoses (NCL) (infantile NCL (INCL), late infantile NCL (LINCL),juvenile NCL (JNCL) or adult NCL (ANCL)), Alzheimer's Disease(Early-onset Alzheimer's, Late-onset Alzheimer's, and FamilialAlzheimer's disease (FAD)), Optic neuritis (ON), Leber's hereditaryoptic neuropathy (LHON), Autism Spectrum Disorders (ASD) (Asperger'sSyndrome, Pervasive Developmental Disorders (PDDs), ChildhoodDisintegrative Disorder (CDD), and Autistic disorder), Rett syndrome,Angelman's Syndrome, Leigh disease, Prader Willi Syndrome, Fragile-XSyndrome, Depression (Major Depression, Dysthymia, PostpartumDepression, Seasonal Affective Disorder, Atypical Depression, PsychoticDepression, Bipolar Disorder, Premenstrual Dysphoric Disorder,Situational Depression), Parkinson's disease (Idiopathic Parkinson'sdisease, Vascular parkinsonism, Dementia with Lewy bodies, InheritedParkinson's, Drug-induced Parkinsonism, Juvenile Parkinson's andatypical parkinsonism), mitochondrial diseases, developmental disorders,metabolic syndrome (increased blood pressure, high blood sugar level,excess body fat around the waist and abnormal cholesterol levels) and/orautoimmune disorders by inducing BDNF mRNA expression and protein levelswith DNP treatment to reverse, slow or prevent neuromuscular and/orneurodegeneration and/or muscle wasting.

In another embodiment, the present invention relates to a composition ofDNP, or a pharmaceutically acceptable salt, solvate, or hydrate thereof,comprising an effective dose of DNP, wherein the effective dose of theDNP is in the range of 0.001 mg/kg of body weight to 5 mg/kg of bodyweight.

In yet another embodiment, the present invention relates to apharmaceutical composition of DNP, or a pharmaceutically acceptablesalt, solvate, or hydrate thereof, comprising a unit dose, wherein theunit dose is in the range of 0.1 mg to 300 mg.

In yet another embodiment, the present invention relates to a method oftreating neuromuscular or autoimmune or developmental orneurodegenerative or metabolic disorders, comprising receiving aneffective dose of DNP, or a pharmaceutically acceptable salt thereof,over period sufficiently long to achieve remission of the symptoms ofthe disease, wherein the effective dose of the DNP is continued to bereceived in the dose range of 0.001 mg/kg of body weight to 5 mg/kg ofbody weight to increase BDNF to attenuate disease progression or provideremission of symptoms.

A fifth aspect of the present invention relates to a method of treatingneuromuscular or autoimmune or developmental or metabolic orneurodegenerative disorders, comprising: providing instructions toadminister an effective dose of DNP, or a pharmaceutically acceptablesalt thereof, over period sufficiently long to achieve remission of thesymptoms of the disease, wherein the effective dose of the DNP isinstructed to be received in the dose range of 0.001 mg/kg of bodyweight to 5 mg/kg of body weight.

BRIEF DESCRIPTION OF THE FIGURES

The present invention will be better understood by examining thefollowing figures which illustrate certain properties of the presentinvention wherein:

FIG. 1 depicts a chart showing that administration of DNP increases BDNFlevels in the brain, in accordance with embodiments of the presentinvention.

FIG. 2a depicts the changes of BDNF protein levels by immunoblot from amouse model of MS, Experimental Autoimmune encephalomyelitis.

FIG. 2b depicts the percent change of BDNF protein levels from a mousemodel of MS based on an immunoblot study.

FIG. 2c depicts the effect of MP101 on progression of the phenotype inthe MS model on clinical scores showing attenuation of diseaseprogression.

FIG. 2d depicts a representative mouse spinal cord electron microscopyimage at Day-16 (peak of onset) for a mouse treated with 5 mg/kg ofMP101 compared to placebo.

FIG. 3a depicts the results of a study involving Mecp2 mutant mice, amodel of Rett Syndrome, after treatment with DNP at 6-weeks of age.

FIG. 3b depicts the results of a study involving Mecp2 mutant mice, amodel of Rett Syndrome, after treatment with DNP at 12-weeks of age.

FIG. 4 depicts the results of a study involving Mecp2 mutant mice at12-weeks of age after 1-month of oral gavage treatment, which shows aneffect in the “clasping test” at 1 mg/kg DNP.

FIGS. 5a, 5b and 5c depict the results of a study involving APP/PS1 miceat 4-months of age after 4-months treatment by oral gavage delivery withDNP in an Alzheimer's study

FIG. 6 depicts the results of a mouse study whereby mice were treatedwith DNP for 2-weeks at 1, 5 and 10 mg/kg by oral gavage and thenprovide a kanic acid injection into the brain to determine the impact onseizure time.

FIG. 7a depicts the results of a mouse study whereby mice were treatedwith DNP for 14 days to see the impact on protecting dopaminergicneuronal loss.

FIG. 7b depicts the results of another mouse study whereby mice weretreated with DNP for 14 days to see the impact on protectingdopaminergic neuronal loss.

FIG. 8a depicts an MRI image of brain volume changes of wildtype (WT),mutant Huntington mice Vehicle (HD) with DNP treatment.

FIG. 8b depicts the quantitative brain volume loss in the cortex afterDNP treatment.

FIG. 8c shows the quantitative brain volume loss in the striatum afterDNP treatment.

FIG. 8d depicts the results of a mouse study showing that treatment withDNP preserves medium spiny neurons using biomarker DARPP32 at 26-weeksof age.

FIG. 8e depicts the results of a mouse study showing that treatment withDNP preserves general neuronal loss with biomarker to postsynapticprotein PSD95 levels in N171-82Q HD mice.

FIG. 8f depicts the results of a mouse study showing that treatment withDNP improves motor function in both the taper beam and balance beamafter 17-weeks of treatment.

DETAILED DESCRIPTION OF THE INVENTION

Hereinafter, the term “endogenous”, unless otherwise defined, meansgrowing or produced by growth from deep tissue, e.g. by growth from aperson's brain. Alternatively, the term “endogenous”, unless otherwisedefined, means caused by factors inside the organism or system.Alternatively, the term “endogenous”, unless otherwise defined, meansproduced or synthesized within the organism or system.

Hereinafter, unless otherwise defined, the term “muscle wasting” meansatrophy of a person's muscle (e.g. diaphragm for breathing). Muscleatrophy is when muscles waste away. The main reason for muscle wastingis a lack of physical activity. This can happen when a disease or injurymakes it difficult or impossible for you to move an arm or leg.

Hereinafter, unless otherwise defined, the terms “effective dose” or“effective relief” are measured objectively using one or more of thefollowing quantitative assessments to achieve a validated assessment ofthe effectiveness of the dose or relief: ADS COG for Alzheimer'sDisease; HDRS for Huntington's Disease; the Parkinson Rating Scale forParkinson's Disease; the FSS and EDSS for Multiple Sclerosis; the ALSAQfor ALS; Stroke Assessment Scales of Stroke such as the NIH Stroke Scaleor Barthel Index; Childhood Autism Rating Scale (CARS) for Autism;6-minute walk test for Duchenne muscular dystrophy (DMD); and a seizureseverity scale for seizures.

Hereinafter, unless otherwise defined, the term “about” means plus orminus 10% of the value referenced. For example, “about 1 mg/kg” means0.9 mg/kg to 1.1 mg/kg.

Mitochondria uncouplers, e.g., 2,4-dinitrophenol (DNP), may beadvantageously administered as a therapeutic approach forneuroprotection in cases of traumatic CNS injury, neurodegenerativedisease, autoimmune disease, developmental disorders, and metabolicdisease. Mitochondria uncoupling can have a protective effect on braincells by enhancing respiratory rates by mild uncoupling which leads tolower cellular stress due to a mechanism of action (MOA) of: 1)increasing oxygen (O₂) consumption, which prevents formation ofsuperoxide radical anions (O₂ ⁻) by decreasing O₂ tension in themicroenvironment, 2) providing more oxidized levels of respiratory chainintermediates, such as in Complex I and III, known as a substantialsource of reactive oxygen species (ROSs), 3) maintaining NADH levelslower, which prevents ROS formation by mitochondrial matrixflavoproteins and 4) lower membrane potential (Δψ), a condition whichthermodynamically disfavors reverse of electron transfer from Complex IIto I.

Further, neurite outgrowth may, in theory, be achieved with the use ofuncouplers beyond the use for lowering ROSs. It is known that DNP canlower ROSs species with an acute single dose post-ischemia, and reduceinfarct volume, however the benefits of improved outcome and recovery byrepair can be accomplished with increasing expression of BDNF, requiringchronic treatment to induce sufficient levels of this neurotrophin.Infarct volume may therefore be further reduced from repair/growth ofthe damaged tissue by chronic DNP treatment.

In one embodiment, the present invention relates to the discovery thatBDNF can be endogenously induced to increase expression with thetreatment of DNP, and that there is a dose range of DNP that iseffective and is not too high to be harmful, nor too low and provide noeffect. The effectiveness of DNP in inducing BDNF does not increaselinearly as the dose of DNP is increased. In one embodiment, we showthat there is a DNP dose amount whereby the beneficial effect no longerincreases, and, significantly, there is a dose amount whereby thebeneficial effect of DNP actually decreases.

While not bound by theory, the mechanism of action for DNP is likelyconversion of a non-genomic event into a genomic event. Mitochondrialuncouplers do not directly act upon a protein, but on a location, namelythe mitochondrial matrix. The mitochondrial matrix is a pH basicenvironment due to the pumping out of protons (hydrogen or H⁺) throughthe cytochromes. Since mitochondrial uncouplers are weak acids with adissociable proton, they are attracted to the basic environment of themitochondrial matrix, where they travel as a cation and drop off aproton (H⁺), then leave unprotonated back into the acidic environment ofcytosol as an anion, to then get reprotonated back to a cation and startthe cycle over again until metabolized and/or eliminated. This eventlowers the mitochondrial membrane potential, which results in anincrease in energy expenditure with the consumption of glucose andlipids in an attempt to re-establish the membrane potential. This effectis considered non-genomic, since DNP does not act directly through aprotein or touch a protein, but just goes into a unique location withinthe cell of which happens to be the only location with a pH basicenvironment. It also lowers intra-mitochondria calcium. Adenylatecyclase, the enzyme that synthesizes 3′5′-cyclic monophosphate (cyclicAMP or cAMP), otherwise known as “second messenger”, is highly sensitiveto changes in calcium and magnesium and it has been shown that DNPup-regulates cAMP supplies. The cascade affect of up-regulatingadenylate cyclase and producing more cAMP, then converts DNP'snon-genomic effect, into a genomic effect, which changes expression of ahost of genes, including increasing the transcription factor for BDNF,known as cAMP-responsive element-binding protein (CREB).

By way of example only, BDNF is lower in Huntington's Disease, andrestoring BDNF to near normal levels is considered to be critical toattenuate disease onset. Therefore, treatment with DNP that effectivelycrosses the blood brain barrier and induces endogenous expression ofBDNF is advantageous for treating diseases for which increasedexpression of BDNF will provide neuroprotection. Similarly, RettSyndrome is considered a developmental disorder in young girls and isassociated with lower levels of BDNF. Restoring levels back to nearnormal levels may prevent the stunting of head growth that appearsaround approximately 18 months of age as one marker of onset. For otherdiseases, such as multiple sclerosis (MS), the positive effects of BDNFhave not been well studied, but we have shown in a model of MS that BDNFlevels are elevated in the brain and striking axonal protection from theautoimmune disorder that destroys the myelin sheaths under chronictreatment of DNP. Others have shown that BDNF can lower glucose levelsin models of obesity and diabetes. Others have found that young,non-obese insulin resistant patients have low circulating levels ofBDNF, which acts as a paracrine and may be a factor in the metabolicsyndrome. Therefore, an elevated and sustained increase in BDNF mayprovide a broad effect in neurodegeneration, development, autoimmune,metabolic and neuromuscular disorders. In addition, an increase of BDNFin both central and/or peripheral compartments may be beneficial.

In addition to the brain, BDNF is also expressed in other muscle tissuesand thought to act as a myokine to provide neuromuscular or muscleprotection, in addition to protection from neurodegeneration.

Surprisingly, the dose range of about 0.001 to 5 mg/kg has been shown tobe effective in treating muscular, neuromuscular, neurodegenerative,autoimmune, developmental and/or metabolic diseases, such as, forexample, traumatic injury, stroke, Huntington's disease, Epilepsy,Multiple Sclerosis (MS), Lupus, Type-1 and Type-2 diabetes, MODY,metabolic syndrome, Duchenne Muscular Dystrophy (DMD), severe burns,aging, Amyotrophic Lateral Sclerosis (ALS), Friedreich's Ataxia, BattenDisease, Alzheimer's disease, Optic neuritis, Autism, Rett syndrome,Batten Disease, Angelman's Syndrome, Fragile-X Syndrome, Schizophrenia,Depression, and Parkinson's disease. In one embodiment, the inventionshows use of DNP in the effective dose range of about 0.01 to less than10 mg/kg to induce expression of BDNF in the brain of mammals, whichavoid inducing too much BDNF to be harmful, or have no effect byinducing too little BDNF.

As described herein below, mitochondrial uncoupler DNP was tested in arange of doses in mice from 0.5 mg/kg of DNP to 10 mg/kg of DNP underoral chronic treatment to titrate the amount of drug in the brainrequired to induce increases of BDNF endogenously within the brain. Itwas discovered that DNP does in fact induce BDNF within the brain, butthe highest dose of 10 mg/kg had a reduced level of BDNF compared withthe next two lower doses. Therefore, it was discovered that there is aspecific and limited dose range of DNP that is necessary to achievestatistically significant survival and behavioral benefit for a host ofdiseases that benefit from increased BDNF levels. In one embodiment,diseases and disorders of the systemic organs and brain, islets ofLangerhans, liver and brain may benefit from titrating the BDNF levelswith a specific and limited DNP dose, such as, but not limited to,Traumatic Brain Injury (TBI), Ischemic stroke, Huntington's disease(Adult-onset Huntington's, Juvenile Huntington's disease), Epilepsy(Cluster Seizures, Refractory Seizures, Atypical Absence Seizures,Atonic Seizures, Clonic Seizures, myoclonic seizures, tonic seizures,Tonic-Clonic Seizures, Simple Partial Seizures, Complex PartialSeizures, Secondary Generalized Seizures, Febrile Seizures, NonepilepticSeizures, Gelastic and Dacrystic Seizures, and Absence Seizures),Multiple Sclerosis (MS) (relapse-remitting multiple sclerosis (RRMS),Secondary-progressive MS (SPMS), Primary-progressive MS (PPMS), andProgressive-relapsing MS (PRMS)), Lupus (Systemic Lupus Erythematosus(SLE), discoid (cutaneous), drug-induced lupus (dil) and neonatallupus), Diabetes mellitus (Type-1 Diabetes, Type-2 Diabetes, MaturityOnset Diabetes of the Young (MODY: MODY1, MODY2, MODY3, MODY4, MODY5,MODY6, MODY7, MODY8, MODY9, MODY10, MODY11)), Schizophrenia (Paranoidschizophrenia, Disorganized schizophrenia, Catatonic schizophrenia,Residual schizophrenia, Schizoaffective disorder), Myasthenia gravis(MG) (ocular myasthenia gravis, Congenital MG and generalized myastheniagravis), rheumatoid arthritis (RA), Graves' disease, Guillain-Barrésyndrome (GBS), Muscular Dystrophy (Duchenne Muscular Dystrophy (DMD),Becker, Myotonic, Congenital, Emery-Dreifuss, Facioscapulohumeral,Limb-girdle, Distal, and Oculopharyngeal), severe burns, aging,Amyotrophic Lateral Sclerosis (ALS), Ataxia (Friedreich's Ataxia,Spinocerebellar ataxias 1 (SCA1), Spinocerebellar ataxias 2 (SCA2),Spinocerebellar ataxias 3 (SCA3), Spinocerebellar ataxias 6 (SCA6),Spinocerebellar ataxias 7 (SCAT), Spinocerebellar ataxias 11 (SCA11),Dentatorubral pallidolusyian atrophy (DRPLA) and Gluten ataxia), BattenDisease or neuronal ceroid lipofuscinoses (NCL) (infantile NCL (INCL),late infantile NCL (LINCL), juvenile NCL (JNCL) or adult NCL (ANCL)),Alzheimer's Disease (Early-onset Alzheimer's, Late-onset Alzheimer's,and Familial Alzheimer's disease (FAD)), Optic neuritis (ON), Leber'shereditary optic neuropathy (LHON), Autism Spectrum Disorders (ASD)(Asperger's Syndrome, Pervasive Developmental Disorders (PDDs),Childhood Disintegrative Disorder (CDD), and Autistic disorder), Rettsyndrome, Angelman's Syndrome, Leigh disease, Prader Willi Syndrome,Fragile-X Syndrome, Depression (Major Depression, Dysthymia, PostpartumDepression, Seasonal Affective Disorder, Atypical Depression, PsychoticDepression, Bipolar Disorder, Premenstrual Dysphoric Disorder,Situational Depression), Parkinson's disease (Idiopathic Parkinson'sdisease, Vascular parkinsonism, Dementia with Lewy bodies, InheritedParkinson's, Drug-induced Parkinsonism, Juvenile Parkinson's andatypical parkinsonism), mitochondrial diseases, developmental disorders,metabolic syndrome (increased blood pressure, high blood sugar level,excess body fat around the waist and abnormal cholesterol levels) and/orautoimmune disorders.

Wildtype C57BL/6J mice were treated with 2,4-dinitrophenol for two weeksdaily by oral gavage at 0.5, 1.0, 5.0, and 10.0 mg/kg DNP or placebo,N=8 per group. Brain tissue was used for semi quantitative polymerasechain reaction (PCR) to determine endogenous BDNF levels normalized toGapDH to determine delta-delta CT changes in mRNA. Data shows thedelta-delta CT change for each dose level of DNP expressed as a percentchange relative to the control group, which was given a placebo.

FIG. 1 shows that administration of DNP in Wildtype Mouse increases BDNFlevels in the brain between 0.1 mg/kg DNP and 10 mg/kg DNP, and we haveidentified a bell-shaped curve such that at the higher dose of 10.0mg/kg DNP, less BDNF is expressed. In one embodiment, a higher doserange of DNP may benefit patient populations that are in need of higherBDNF levels, such as Huntington's Disease, Rett Syndrome, Epilepsy, andMultiple Sclerosis (MS), and other forms of neurodegeneration and muscleor neuromuscular disorders, since BDNF is a myokine and can provide apositive benefit to muscle wasting.

FIG. 2a shows the changes of BDNF protein levels by immunoblot from amouse model of MS, Experimental Autoimmune Encephalomyelitis (EAE). Thetissue was taken on Day 42 of the study during the recovery phase fromthe lumbal spinal cord of representative mice that were immunized on Day1 with the MOG peptide, then treated with MP101 starting on Day 7 andstopping on Day 21. Intensity of the BDNF band increases from placebo,to 0.5 mg/kg, to 1 mg/kg, with a plateau effect at 5 mg/kg. Untreatedanimals are shown as naïve. The changes in BDNF levels are therefore3-weeks post-treatment with DNP (aka MP101). DNP not only increasesBDNF, but the effect of increasing BDNF has a lasting effect that is notobvious until now.

FIG. 2b shows the percent changes of BDNF protein levels by immunoblotfrom a mouse model of MS, Experimental Autoimmune encephalomyelitis(EAE) 3-weeks post-treatment.

FIG. 2c shows the effect of MP101 on progression of the phenotype in theMS model on clinical scores showing attenuation of disease progression.

FIG. 2d shows a representative mouse spinal cord electron microscopyimage at Day-16 (˜peak of onset) of MP101 5 mg/kg treated mouse comparedto placebo. The protective myelin sheaths surrounding the axons andaxons are completely intact as compared to the placebo group.

Therefore, we have tested DNP to induce BDNF in the brain of wildtypemodel by mRNA changes and tested DNP to increase BDNF at the proteinlevel with a demonstration of providing a protective effect in a modelof MS, the Experimental Autoimmune Encephalomyelitis (EAE).

MP101 was tested in a model of Rett Syndrome using Mecp2 mutant mice.Rett Syndrome is a developmental disorder in young girls, with firstsymptoms starting at about 18-months of age, including reduced headgrowth. FIGS. 3a, 3b, 3c and 4 show the effects of treating these mutantmice with MP101 at 0.5, 1 mg/kg and 5 mg/kg by oral gavage.

In FIGS. 3a and 3b , Mecp2 mutant mice, a model of Rett Syndrome, weretreated with MP101 (DNP) at 6-weeks of age and tested on theircoordination to walk on a rotating cylinder (rotarod). Wildtype mice areused as a benchmark for general decline in behavior compared to Mecp2mutant mice treated with Vehicle, 0.5 mg/kg MP101, 1 mg/kg MP101 and 5mg/kg MP101 by oral gavage. In FIG. 3a , the data shows that at 8-weeksof age, the mutant vehicle treated mice lost their ability to walk onthe rotarod, whereas the wildtype mice and drug treated animals fallless and can handle higher speeds of rotation. In FIG. 3b , the datashows similar findings at Week-12 of age after 1-month of treatment.

In FIG. 4, we show the results of Mecp2 mutant mice at 12-weeks of ageand after 1-month of oral gavage treatment, which shows an effect in the“clasping test” at 1 mg/kg MP101.

In addition, Alzheimer's Disease, representing about 70% of all dementiacases, was evaluated using the APP/PS1 mice, which express the APPswemutation and PS1deltaE9 mutation and develop relatively rapid Aβpathology and cognitive deficits. At 4-months of age, the APP/PS1 micewere treated for 4-months by oral gavage delivery with MP101 (DNP) at0.5, 1 and 5 mg/kg. FIGS. 5a, 5b and 5c show that MP101 have improvedcognition compared to Vehicle treated mice. The amount of time spent inthe quadrant is an indicator of whether the mice remember the generallocation, with increased time indicating increased memory.

FIGS. 5a, 5b and 5c show that at all doses with DNP, the APP/PS1 miceimproved in short term memory when tested on the Morris Water Maze forcognition in remembering where the hidden platform was, relative tovehicle which could not. FIG. 5a shows the distance traveled looking forthe platform in the quadrant with the hidden platform, FIG. 5b shows theamount of time spent in the quadrant where the platform is hidden, andFIG. 5c shows the number of entries from the platform. The amount oftime spent in the quadrant is an indicator of whether the subjectremembers the general location.

DNP was also evaluated for a treatment of Epilepsy. The kanic acid modelis an acute model of epilepsy caused by an injection in the righthippocampus of an analogue of glutamate (kanic acid) thatover-stimulates the neurons causing death. FIG. 6 shows the effect oftreating wildtype mice for 14-days by oral gavage at 1, 5 and 10 mg/kgwith MP101 (DNP), prior to injection of kanic acid to determine if DNPas a protective effect to the effects on over-stimulation and death bykanic acid.

FIG. 6 shows that after 2-weeks of treatment with MP101 (DNP) at 1, 5and 10 mg/kg by oral gavage and then a kanic acid injection into thebrain of a mouse, there is a shortening of seizure time. DNP providedneural protection from over-stimulation caused by kanic acid relative tothe Vehicle.

The merits of treating Parkinson's Disease with MP101 (DNP) wasevaluated in wildtype mice and SIRT3 KO mice with 6-OHDA injectionsafter two weeks of MP101 treatment. We examined the neuroprotectiveeffects of varying MP-101 doses (0.5, 1, 5 mg/kg) against dopaminergicdegeneration of nigrostriatal neurons induced by a single unilateralstereotaxic injection of neurotoxin 6-hydroxydopamine (6-OHDA) in theright striatum of the brain of 2-3 month old male C57Bl/6 mice or SIRT3KO mice. SIRT3 KO is a model of a heightened sensitivity toglutamate-induced calcium overload and excitotoxicity, and oxidative andmitochondrial stress, therefore ideal for evaluating Parkinson'sDisease, Huntington's Disease and temporal lobe epilepsy. FIG. 7 showsthat MP101 protected the dopaminergic neurons from the toxic effects of6-OHDA.

FIGS. 7a and 7b show the effects of DNP (MP101) treatment for 14-Days byoral gavage in protecting dopaminergic neuronal loss when the rightstriatum is injected with 6-OHDA after the last day. FIG. 7a show thatwhen the mice are placed in a cylinder, the percent of left and rightpaw touches on the wall is improved in wildtype mice, and FIG. 7b showsthat in the SIRT3 KO mice, which are more vulnerable to Parkinson'sdisease, there is improved motor coordination when treated with MP101(DNP) and placed on a rotating cylinder (rotarod).

MP101 (DNP) was used in a mouse model of Huntington's Disease, the“Fragment Model” N171-82 HD mice, to determine its neuroprotectiveeffects. The N171-82 HD mice were treated with MP101 at 0.5, 1 and 5mg/kg by oral gavage daily for greater than 17-weeks. At the age of26-weeks (17-weeks of treatment), the mice were tested for changes inbehavioral, loss of brain volume, spiny neurons and general neurons.FIGS. 8a, 8b, 8c, 8d, 8e, and 8f show the effects of DNP (MP101 drugtreatment).

FIGS. 8a-8f show the effects of MP101 in the Huntington's Disease modelN171-82Q after 13-weeks (age 22 weeks) and/or 17-weeks (age 26-weeks) oftreatment with DNP. FIG. 8a shows an MM image of brain volume changes ofwildtype (WT), mutant Huntington mice Vehicle (HD) and MP101 treatedmice (HD-MP101). FIG. 8b shows the quantitative brain volume loss in thecortex. FIG. 8c shows the quantitative brain volume loss in thestriatum. HD placebo (HD) shows loss in both Ctx and Str. MP-101 showsminor loss in cortex and striatum. FIG. 8d shows that treatment with DNPpreserves medium spiny neurons using biomarker DARPP32 at 26-weeks ofage. FIG. 8e shows that treatment with DNP preserves general neuronalloss with biomarker to postsynaptic protein PSD95 levels in N171-82Q HDmice. FIG. 8f shows that treatment with DNP improves motor function inboth the tapered beam and balance beam after 17-weeks of treatment.

In view of the foregoing, the present invention describes methods andformulations related to the effective use of DNP to increase BDNF toattenuate disease progression or provide remission of symptoms incertain diseases.

Method of Use

In one embodiment, a method of use of the invention may include a methodof treating a neurodegenerative, neuromuscular, developmental,metabolic, auto-immune or mitochondrial disorder, including thoserelated to aging, comprising administering to a patient in need oftreatment an effective dose of DNP, or a pharmaceutically acceptablesalt thereof, over a period sufficiently long to achieve remission ofthe symptoms of the disease, wherein the effective dose of the DNP iscontinued in the dose range of 0.001 mg/kg of body weight to 5 mg/kg ofbody weight to increase BDNF to attenuate disease progression or provideremission of symptoms.

In one embodiment, a method of use of the invention may include a methodof treating a neurodegenerative, neuromuscular, developmental,metabolic, autoimmune or mitochondrial disorder, including those relatedto aging, comprising administering to a patient in need of treatment aneffective dose of DNP, or a pharmaceutically acceptable salt thereof,over a period sufficiently long to achieve remission of the symptoms ofthe disease, wherein the effective dose of the DNP is continued in thedose range of about 0.001 mg/kg of body weight to about 5 mg/kg of bodyweight to increase BDNF to attenuate disease progression or provideremission of symptoms.

In one embodiment, a method of use of the invention may include a methodof treating a neurodegenerative, neuromuscular, developmental,metabolic, auto-immune or mitochondrial disorder, including thoserelated to aging and any of the aforementioned diseases or conditions,comprising administering to a patient in need of treatment an effectivedose of DNP, or a pharmaceutically acceptable salt thereof, over aperiod sufficiently long to achieve remission of the symptoms of thedisease, wherein the effective dose of the DNP is continued in the doserange of 0.01 mg/kg of body weight to 5 mg/kg of body weight to increaseBDNF to attenuate disease progression or provide remission of symptoms.

In one embodiment, a method of use of the invention may include a methodof treating a neurodegenerative, neuromuscular, developmental,metabolic, auto-immune or mitochondrial disorder, including thoserelated to aging and any of the aforementioned diseases or conditions,comprising administering to a patient in need of treatment an effectivedose of DNP, or a pharmaceutically acceptable salt thereof, over aperiod sufficiently long to achieve remission of the symptoms of thedisease, wherein the effective dose of the DNP is continued in the doserange of about 0.01 mg/kg of body weight to about 5 mg/kg of body weightto increase BDNF to attenuate disease progression or provide remissionof symptoms.

In one embodiment, a method of use of the invention may include a methodof treating a neurodegenerative, neuromuscular, developmental,metabolic, auto-immune or mitochondrial disorder, including thoserelated to aging and any of the aforementioned diseases or conditions,comprising administering to a patient in need of treatment an effectivedose of DNP, or a pharmaceutically acceptable salt thereof, over aperiod sufficiently long to achieve remission of the symptoms of thedisease, wherein the effective dose of the DNP is continued in the doserange of 0.01 mg/kg of body weight to 1 mg/kg of body weight to increaseBDNF to attenuate disease progression or provide remission of symptoms.

In one embodiment, a method of use of the invention may include a methodof treating a neurodegenerative, neuromuscular, developmental,metabolic, auto-immune or mitochondrial disorder, including thoserelated to aging and any of the aforementioned diseases or conditions,comprising administering to a patient in need of treatment an effectivedose of DNP, or a pharmaceutically acceptable salt thereof, over aperiod sufficiently long to achieve remission of the symptoms of thedisease, wherein the effective dose of the DNP is continued in the doserange of about 0.01 mg/kg of body weight to about 1 mg/kg of body weightto increase BDNF to attenuate disease progression or provide remissionof symptoms.

In one embodiment, a method of use of the invention may include a methodof treating a neurodegenerative, neuromuscular, developmental,metabolic, auto-immune or mitochondrial disorder, including thoserelated to aging and any of the aforementioned diseases or conditions,comprising administering to a patient in need of treatment an effectivedose of DNP, or a pharmaceutically acceptable salt thereof, over aperiod sufficiently long to achieve remission of the symptoms of thedisease, wherein the effective dose of the DNP is continued in the doserange of 0.005 mg/kg of body weight to 2 mg/kg of body weight toincrease BDNF to attenuate disease progression or provide remission ofsymptoms.

In one embodiment, a method of use of the invention may include a methodof treating a neurodegenerative, neuromuscular, developmental,metabolic, auto-immune or mitochondrial disorder, including thoserelated to aging and any of the aforementioned diseases or conditions,comprising administering to a patient in need of treatment an effectivedose of DNP, or a pharmaceutically acceptable salt thereof, over aperiod sufficiently long to achieve remission of the symptoms of thedisease, wherein the effective dose of the DNP is continued in the doserange of about 0.005 mg/kg of body weight to about 2 mg/kg of bodyweight to increase BDNF to attenuate disease progression or provideremission of symptoms.

In one embodiment, a method of use of the invention may include a methodof treating a neurodegenerative, neuromuscular, developmental,metabolic, autoimmune or mitochondrial disorder, including those relatedto aging and any of the aforementioned diseases or conditions,comprising administering to a patient in need of treatment an effectivedose of DNP, or a pharmaceutically acceptable salt thereof, over aperiod sufficiently long to achieve remission of the symptoms of thedisease, wherein the effective dose of the DNP is continued in the doserange of 0.02 mg/kg of body weight to 0.9 mg/kg of body weight toincrease BDNF to attenuate disease progression or provide remission ofsymptoms.

In one embodiment, a method of use of the invention may include a methodof treating a neurodegenerative, neuromuscular, developmental,metabolic, autoimmune or mitochondrial disorder, including those relatedto aging and any of the aforementioned diseases or conditions,comprising administering to a patient in need of treatment an effectivedose of DNP, or a pharmaceutically acceptable salt thereof, over aperiod sufficiently long to achieve remission of the symptoms of thedisease, wherein the effective dose of the DNP is continued in the doserange of about 0.02 mg/kg of body weight to about 0.9 mg/kg of bodyweight to increase BDNF to attenuate disease progression or provideremission of symptoms.

In one embodiment, a method of use of the invention may include a methodof treating a neurodegenerative, neuromuscular, developmental,metabolic, autoimmune or mitochondrial disorder, including those relatedto aging and any of the aforementioned diseases or conditions,comprising administering to a patient in need of treatment an effectivedose of DNP, or a pharmaceutically acceptable salt thereof, over aperiod sufficiently long to achieve remission of the symptoms of thedisease, wherein the effective dose of the DNP is continued in the doserange of 0.02 mg/kg of body weight to 0.06 mg/kg of body weight toincrease BDNF to attenuate disease progression or provide remission ofsymptoms.

In one embodiment, a method of use of the invention may include a methodof treating a neurodegenerative, neuromuscular, developmental,metabolic, autoimmune or mitochondrial disorder, including those relatedto aging and any of the aforementioned diseases or conditions,comprising administering to a patient in need of treatment an effectivedose of DNP, or a pharmaceutically acceptable salt thereof, over aperiod sufficiently long to achieve remission of the symptoms of thedisease, wherein the effective dose of the DNP is continued in the doserange of about 0.02 mg/kg of body weight to about 0.06 mg/kg of bodyweight to increase BDNF to attenuate disease progression or provideremission of symptoms.

In one embodiment, a method of use of the invention may include a methodof treating a neurodegenerative, neuromuscular, developmental,metabolic, autoimmune or mitochondrial disorder, including those relatedto aging and any of the aforementioned diseases or conditions,comprising administering to a patient in need of treatment an effectivedose of DNP, or a pharmaceutically acceptable salt thereof, over aperiod sufficiently long to achieve remission of the symptoms of thedisease, wherein the effective dose of the DNP is continued in the doserange of 0.05 mg/kg of body weight to 0.09 mg/kg of body weight toincrease BDNF to attenuate disease progression or provide remission ofsymptoms.

In one embodiment, a method of use of the invention may include a methodof treating a neurodegenerative, neuromuscular, developmental,metabolic, autoimmune or mitochondrial disorder, including those relatedto aging and any of the aforementioned diseases or conditions,comprising administering to a patient in need of treatment an effectivedose of DNP, or a pharmaceutically acceptable salt thereof, over aperiod sufficiently long to achieve remission of the symptoms of thedisease, wherein the effective dose of the DNP is continued in the doserange of about 0.05 mg/kg of body weight to about 0.09 mg/kg of bodyweight to increase BDNF to attenuate disease progression or provideremission of symptoms.

In one embodiment, a method of use of the invention may include a methodof treating a neurodegenerative, neuromuscular, developmental,metabolic, autoimmune or mitochondrial disorder, including those relatedto aging and any of the aforementioned diseases or conditions,comprising administering to a patient in need of treatment an effectivedose of DNP, or a pharmaceutically acceptable salt thereof, over aperiod sufficiently long to achieve remission of the symptoms of thedisease, wherein the effective dose of the DNP is continued in the doserange of 0.2 mg/kg of body weight to 0.6 mg/kg of body weight toincrease BDNF to attenuate disease progression or provide remission ofsymptoms.

In one embodiment, a method of use of the invention may include a methodof treating a neurodegenerative, neuromuscular, developmental,metabolic, autoimmune or mitochondrial disorder, including those relatedto aging and any of the aforementioned diseases or conditions,comprising administering to a patient in need of treatment an effectivedose of DNP, or a pharmaceutically acceptable salt thereof, over aperiod sufficiently long to achieve remission of the symptoms of thedisease, wherein the effective dose of the DNP is continued in the doserange of about 0.2 mg/kg of body weight to about 0.6 mg/kg of bodyweight to increase BDNF to attenuate disease progression or provideremission of symptoms.

In one embodiment, a method of use of the invention may include a methodof treating a neurodegenerative, neuromuscular, developmental,metabolic, autoimmune or mitochondrial disorder, including those relatedto aging and any of the aforementioned diseases or conditions,comprising administering to a patient in need of treatment an effectivedose of DNP, or a pharmaceutically acceptable salt thereof, over aperiod sufficiently long to achieve remission of the symptoms of thedisease, wherein the effective dose of the DNP is continued in the doserange of 0.5 mg/kg of body weight to 0.9 mg/kg of body weight toincrease BDNF to attenuate disease progression or provide remission ofsymptoms.

In one embodiment, a method of use of the invention may include a methodof treating a neurodegenerative, neuromuscular, developmental,metabolic, autoimmune or mitochondrial disorder, including those relatedto aging and any of the aforementioned diseases or conditions,comprising administering to a patient in need of treatment an effectivedose of DNP, or a pharmaceutically acceptable salt thereof, over aperiod sufficiently long to achieve remission of the symptoms of thedisease, wherein the effective dose of the DNP is continued in the doserange of about 0.5 mg/kg of body weight to about 0.9 mg/kg of bodyweight to increase BDNF to attenuate disease progression or provideremission of symptoms.

In one embodiment, a method of use of the invention may include a methodof treating a neurodegenerative, neuromuscular, developmental,metabolic, autoimmune or mitochondrial disorder, including those relatedto aging and any of the aforementioned diseases or conditions,comprising administering to a patient in need of treatment an effectivedose of DNP, or a pharmaceutically acceptable salt thereof, over aperiod sufficiently long to achieve remission of the symptoms of thedisease, wherein the effective dose of the DNP is continued in the doserange of 0.01 mg/kg of body weight to 0.1 mg/kg of body weight toincrease BDNF to attenuate disease progression or provide remission ofsymptoms.

In one embodiment, a method of use of the invention may include a methodof treating a neurodegenerative, neuromuscular, developmental,metabolic, autoimmune or mitochondrial disorder, including those relatedto aging and any of the aforementioned diseases or conditions,comprising administering to a patient in need of treatment an effectivedose of DNP, or a pharmaceutically acceptable salt thereof, over aperiod sufficiently long to achieve remission of the symptoms of thedisease, wherein the effective dose of the DNP is continued in the doserange of about 0.01 mg/kg of body weight to about 0.1 mg/kg of bodyweight to increase BDNF to attenuate disease progression or provideremission of symptoms.

In one embodiment, a method of use of the invention may include a methodof treating a neurodegenerative, neuromuscular, developmental,metabolic, autoimmune or mitochondrial disorder, including those relatedto aging and any of the aforementioned diseases or conditions,comprising administering to a patient in need of treatment an effectivedose of DNP, or a pharmaceutically acceptable salt thereof, over aperiod sufficiently long to achieve remission of the symptoms of thedisease, wherein the effective dose of the DNP is continued in the doserange of 0.01 mg/kg of body weight to 0.5 mg/kg of body weight toincrease BDNF to attenuate disease progression or provide remission ofsymptoms.

In one embodiment, a method of use of the invention may include a methodof treating a neurodegenerative, neuromuscular, developmental,metabolic, autoimmune or mitochondrial disorder, including those relatedto aging and any of the aforementioned diseases or conditions,comprising administering to a patient in need of treatment an effectivedose of DNP, or a pharmaceutically acceptable salt thereof, over aperiod sufficiently long to achieve remission of the symptoms of thedisease, wherein the effective dose of the DNP is continued in the doserange of about 0.01 mg/kg of body weight to about 0.5 mg/kg of bodyweight to increase BDNF to attenuate disease progression or provideremission of symptoms.

In one embodiment, a method of use of the invention may include a methodof treating a neurodegenerative, neuromuscular, developmental,metabolic, autoimmune or mitochondrial disorder, including those relatedto aging and any of the aforementioned diseases or conditions,comprising administering to a patient in need of treatment an effectivedose of DNP, or a pharmaceutically acceptable salt thereof, over aperiod sufficiently long to achieve remission of the symptoms of thedisease, wherein the effective dose of the DNP is continued in the doserange of 0.05 mg/kg of body weight to 0.5 mg/kg of body weight toincrease BDNF to attenuate disease progression or provide remission ofsymptoms.

In one embodiment, a method of use of the invention may include a methodof treating a neurodegenerative, neuromuscular, developmental,metabolic, autoimmune or mitochondrial disorder, including those relatedto aging and any of the aforementioned diseases or conditions,comprising administering to a patient in need of treatment an effectivedose of DNP, or a pharmaceutically acceptable salt thereof, over aperiod sufficiently long to achieve remission of the symptoms of thedisease, wherein the effective dose of the DNP is continued in the doserange of about 0.05 mg/kg of body weight to about 0.5 mg/kg of bodyweight to increase BDNF to attenuate disease progression or provideremission of symptoms.

In one embodiment, a method of use of the invention may include a methodof treating a neurodegenerative, neuromuscular, developmental,metabolic, autoimmune or mitochondrial disorder, including those relatedto aging and any of the aforementioned diseases or conditions,comprising administering to a patient in need of treatment an effectivedose of DNP, or a pharmaceutically acceptable salt thereof, over aperiod sufficiently long to achieve remission of the symptoms of thedisease, wherein the effective dose of the DNP is continued in the doserange of 0.05 mg/kg of body weight to 0.9 mg/kg of body weight toincrease BDNF to attenuate disease progression or provide remission ofsymptoms.

In one embodiment, a method of use of the invention may include a methodof treating a neurodegenerative, neuromuscular, developmental,metabolic, autoimmune or mitochondrial disorder, including those relatedto aging and any of the aforementioned diseases or conditions,comprising administering to a patient in need of treatment an effectivedose of DNP, or a pharmaceutically acceptable salt thereof, over aperiod sufficiently long to achieve remission of the symptoms of thedisease, wherein the effective dose of the DNP is continued in the doserange of about 0.05 mg/kg of body weight to about 0.9 mg/kg of bodyweight to increase BDNF to attenuate disease progression or provideremission of symptoms.

In one embodiment, a method of use of the invention may include a methodof treating a neurodegenerative, neuromuscular, developmental,metabolic, auto-immune or mitochondrial disorder, including thoserelated to aging and any of the aforementioned diseases or conditions,comprising administering to a patient in need of treatment an effectivedose of DNP, or a pharmaceutically acceptable salt thereof, over aperiod sufficiently long to achieve remission of the symptoms of thedisease, wherein the effective dose of the DNP is continued in the doserange of 0.02 mg/kg of body weight to 1 mg/kg of body weight to increaseBDNF to attenuate disease progression or provide remission of symptoms.

In one embodiment, a method of use of the invention may include a methodof treating a neurodegenerative, neuromuscular, developmental,metabolic, auto-immune or mitochondrial disorder, including thoserelated to aging and any of the aforementioned diseases or conditions,comprising administering to a patient in need of treatment an effectivedose of DNP, or a pharmaceutically acceptable salt thereof, over aperiod sufficiently long to achieve remission of the symptoms of thedisease, wherein the effective dose of the DNP is continued in the doserange of about 0.02 mg/kg of body weight to about 1 mg/kg of body weightto increase BDNF to attenuate disease progression or provide remissionof symptoms.

In one embodiment, a method of use of the invention may include a methodof treating a neurodegenerative, neuromuscular, developmental,metabolic, auto-immune or mitochondrial disorder, including thoserelated to aging, comprising administering to a patient in need oftreatment an effective dose of DNP, or a pharmaceutically acceptablesalt thereof, over a period sufficiently long to achieve remission ofthe symptoms of the disease, wherein the effective dose of the DNP iscontinued in the dose range of 0.01 mg/kg of body weight to 0.1 mg/kg ofbody weight to increase BDNF to attenuate disease progression or provideremission of symptoms.

In one embodiment, a method of use of the invention may include a methodof treating a neurodegenerative, neuromuscular, developmental,metabolic, auto-immune or mitochondrial disorder, including thoserelated to aging, comprising administering to a patient in need oftreatment an effective dose of DNP, or a pharmaceutically acceptablesalt thereof, over a period sufficiently long to achieve remission ofthe symptoms of the disease, wherein the effective dose of the DNP iscontinued in the dose range of about 0.01 mg/kg of body weight to about0.1 mg/kg of body weight to increase BDNF to attenuate diseaseprogression or provide remission of symptoms.

In one embodiment, a method of use of the invention may include a methodof treating a neurodegenerative, neuromuscular, developmental,metabolic, auto-immune or mitochondrial disorder, including thoserelated to aging, comprising administering to a patient in need oftreatment an effective dose of DNP, or a pharmaceutically acceptablesalt thereof, over a period sufficiently long to achieve remission ofthe symptoms of the disease, wherein the effective dose of the DNP iscontinued in the dose range of 0.1 mg/kg of body weight to 1 mg/kg ofbody weight to increase BDNF to attenuate disease progression or provideremission of symptoms.

In one embodiment, a method of use of the invention may include a methodof treating a neurodegenerative, neuromuscular, developmental,metabolic, auto-immune or mitochondrial disorder, including thoserelated to aging, comprising administering to a patient in need oftreatment an effective dose of DNP, or a pharmaceutically acceptablesalt thereof, over a period sufficiently long to achieve remission ofthe symptoms of the disease, wherein the effective dose of the DNP iscontinued in the dose range of about 0.1 mg/kg of body weight to about 1mg/kg of body weight to increase BDNF to attenuate disease progressionor provide remission of symptoms.

In one embodiment, a method of use of the invention may include a methodof treating neuromuscular or neurodegenerative disorder related toaging, comprising administering to a patient in need of treatment of atraumatic CNS injury or neurodegenerative disease an effective dose ofDNP, or a pharmaceutically acceptable salt thereof, over a periodsufficiently long to achieve remission of the symptoms of the disease,wherein the effective dose of the DNP is continued in the dose range of1 mg/kg of body weight to 5 mg/kg of body weight to increase BDNF toattenuate disease progression or provide remission of symptoms.

In one embodiment, a method of use of the invention may include a methodof treating neuromuscular or neurodegenerative disorder related toaging, comprising administering to a patient in need of treatment of atraumatic CNS injury or neurodegenerative disease an effective dose ofDNP, or a pharmaceutically acceptable salt thereof, over a periodsufficiently long to achieve remission of the symptoms of the disease,wherein the effective dose of the DNP is continued in the dose range ofabout 1 mg/kg of body weight to about 5 mg/kg of body weight to increaseBDNF to attenuate disease progression or provide remission of symptoms.

In an embodiment, administration of DNP, or a pharmaceuticallyacceptable salt thereof, in any form or combination as described herein,for any purpose as described herein, is in the dose range of about 0.001mg/kg of body weight to about 5 mg/kg of body weight, about 0.001 mg/kgof body weight to about 4 mg/kg of body weight, about 0.001 mg/kg ofbody weight to about 3 mg/kg of body weight, about 0.001 mg/kg of bodyweight to about 0.005 mg/kg of body weight, about 0.005 mg/kg of bodyweight to about 0.01 mg/kg of body weight, about 0.01 mg/kg of bodyweight to about 1 of body weight, about 0.01 mg/kg of body weight toabout 0.1 of body weight, about 0.02 mg/kg of body weight to about 0.08of body weight, about 0.025 mg/kg of body weight to about 0.06 of bodyweight, about 0.03 mg/kg of body weight to about 0.05 of body weight,about 0.05 mg/kg of body weight to about 0.1 of body weight, about 0.04mg/kg of body weight to about 0.06 of body weight, about 0.06 mg/kg ofbody weight to about 0.09 of body weight, about 0.07 mg/kg of bodyweight to about 0.08 of body weight, about 0.09 mg/kg of body weight toabout 0.11 of body weight, about 0.1 mg/kg of body weight to about 0.5of body weight, about 0.2 mg/kg of body weight to about 0.4 of bodyweight, about 0.3 mg/kg of body weight to about 0.5 of body weight,about 0.4 mg/kg of body weight to about 0.6 of body weight, about 0.5mg/kg of body weight to about 1 of body weight, about 0.6 mg/kg of bodyweight to about 0.9 of body weight, about 0.7 mg/kg of body weight toabout 0.8 of body weight, about 0.8 mg/kg of body weight to about 1.2mg/kg of body weight, about 1 mg/kg of body weight to about 5 mg/kg ofbody weight, or about 2 mg/kg of body weight to about 4 of body weight.

In an embodiment, administration of DNP, or a pharmaceuticallyacceptable salt thereof, in any form or combination as described herein,for any purpose as described herein, is in the dose range of 0.001 mg/kgof body weight to 5 mg/kg of body weight, 0.001 mg/kg of body weight to4 mg/kg of body weight, 0.001 mg/kg of body weight to 3 mg/kg of bodyweight, 0.001 mg/kg of body weight to 0.005 mg/kg of body weight, 0.005mg/kg of body weight to 0.01 mg/kg of body weight, 0.01 mg/kg of bodyweight to 1 of body weight, 0.01 mg/kg of body weight to 0.1 of bodyweight, 0.02 mg/kg of body weight to 0.08 of body weight, 0.025 mg/kg ofbody weight to 0.06 of body weight, 0.03 mg/kg of body weight to 0.05 ofbody weight, 0.05 mg/kg of body weight to 0.1 of body weight, 0.04 mg/kgof body weight to 0.06 of body weight, 0.06 mg/kg of body weight to 0.09of body weight, 0.07 mg/kg of body weight to 0.08 of body weight, 0.09mg/kg of body weight to 0.11 of body weight, 0.1 mg/kg of body weight to0.5 of body weight, 0.2 mg/kg of body weight to 0.4 of body weight, 0.3mg/kg of body weight to 0.5 of body weight, 0.4 mg/kg of body weight to0.6 of body weight, 0.5 mg/kg of body weight to 1 of body weight, 0.6mg/kg of body weight to 0.9 of body weight, 0.7 mg/kg of body weight to0.8 of body weight, 0.8 mg/kg of body weight to 1.2 mg/kg of bodyweight, 1 mg/kg of body weight to 5 mg/kg of body weight, or 2 mg/kg ofbody weight to 4 of body weight.

In an embodiment, administration of DNP, or a pharmaceuticallyacceptable salt thereof, in any form or combination as described herein,for any purpose as described herein, is about 0.001 mg/kg, about 0.002mg/kg, about 0.003 mg/kg, about 0.004 mg/kg, about 0.005 mg/kg, about0.006 mg/kg, about 0.007 mg/kg, about 0.008 mg/kg, about 0.009 mg/kg,about 0.01 mg/kg, about 0.015 mg/kg, about 0.02 mg/kg, about 0.025mg/kg, about 0.03 mg/kg, about 0.035 mg/kg, about 0.04 mg/kg, about0.045 mg/kg, about 0.05 mg/kg, about 0.055 mg/kg, about 0.06 mg/kg,about 0.065 mg/kg, about 0.07 mg/kg, about 0.075 mg/kg, about 0.08mg/kg, about 0.085 mg/kg, about 0.09 mg/kg, about 0.095 mg/kg, about 0.1mg/kg, about 0.15 mg/kg, about 0.2 mg/kg, about 0.25 mg/kg, about 0.3mg/kg, about 0.35 mg/kg, about 0.4 mg/kg, about 0.45 mg/kg, about 0.5mg/kg, about 0.55 mg/kg, about 0.6 mg/kg, about 0.65 mg/kg, about 0.7mg/kg, about 0.75 mg/kg, about 0.8 mg/kg, about 0.85 mg/kg, about 0.9mg/kg, about 0.95 mg/kg, about 1.0 mg/kg, about 1.1 mg/kg, about 1.2mg/kg, about 1.3 mg/kg, about 1.4 mg/kg, about 1.5 mg/kg, about 2 mg/kg,about 2.5 mg/kg, about 3 mg/kg, about 3.5 mg/kg, about 4 mg/kg, about4.5 mg/kg, or about 5.0 mg/kg.

In an embodiment, administration of DNP, or a pharmaceuticallyacceptable salt thereof, in any form or combination as described herein,for any purpose as described herein, is 0.001 mg/kg, 0.002 mg/kg, 0.003mg/kg, 0.004 mg/kg, 0.005 mg/kg, 0.006 mg/kg, 0.007 mg/kg, 0.008 mg/kg,0.009 mg/kg, 0.01 mg/kg, 0.015 mg/kg, 0.02 mg/kg, 0.025 mg/kg, 0.03mg/kg, 0.035 mg/kg, 0.04 mg/kg, 0.045 mg/kg, 0.05 mg/kg, 0.055 mg/kg,0.06 mg/kg, 0.065 mg/kg, 0.07 mg/kg, 0.075 mg/kg, 0.08 mg/kg, 0.085mg/kg, 0.09 mg/kg, 0.095 mg/kg, about 0.1 mg/kg, 0.15 mg/kg, 0.2 mg/kg,0.25 mg/kg, 0.3 mg/kg, 0.35 mg/kg, 0.4 mg/kg, 0.45 mg/kg, 0.5 mg/kg,0.55 mg/kg, 0.6 mg/kg, 0.65 mg/kg, 0.7 mg/kg, 0.75 mg/kg, 0.8 mg/kg,0.85 mg/kg, 0.9 mg/kg, 0.95 mg/kg, 1.0 mg/kg, 1.1 mg/kg, 1.2 mg/kg, 1.3mg/kg, 1.4 mg/kg, 1.5 mg/kg, 2 mg/kg, 2.5 mg/kg, 3 mg/kg, 3.5 mg/kg, 4mg/kg, 4.5 mg/kg, or 5.0 mg/kg.

In an embodiment, administration of DNP, or a pharmaceuticallyacceptable salt thereof, in any form or combination as described herein,for any purpose as described herein, is about 10 mg/kg of body weight orless, about 5 mg/kg of body weight or less, about 4.5 mg/kg or less,about 4 mg/kg or less, about 3.5 mg/kg or less, about 3 mg/kg or less,about 2.5 mg/kg or less, about 2 mg/kg or less, about 1.5 mg/kg or less,about 1 mg/kg or less, about 0.95 mg/kg or less, about 0.9 mg/kg orless, about 0.85 mg/kg or less, about 0.8 mg/kg or less, about 0.75mg/kg or less, about 0.7 mg/kg or less, about 0.65 mg/kg or less, about0.6 mg/kg or less, about 0.55 mg/kg or less, about 0.5 mg/kg or less,about 0.45 mg/kg or less, about 0.4 mg/kg or less, about 0.35 mg/kg orless, about 0.3 mg/kg or less, about 0.25 mg/kg or less, about 0.2 mg/kgor less, about 0.15 mg/kg or less, about 0.1 mg/kg or less, about 0.09mg/kg or less, about 0.08 mg/kg or less, about 0.07 mg/kg or less, about0.06 mg/kg or less, about 0.05 mg/kg or less, about 0.04 mg/kg or less,about 0.03 mg/kg or less, about 0.02 mg/kg or less, about 0.01 mg/kg orless, or about 0.005 mg/kg or less. In all cases, the doses describedherein are greater than zero mg/kg.

In an embodiment, administration of DNP, or a pharmaceuticallyacceptable salt thereof, in any form or combination as described herein,for any purpose as described herein, is about 4 mg/kg or more, about 3.5mg/kg or more, about 3 mg/kg or more, about 2.5 mg/kg or more, about 2mg/kg or more, about 1.5 mg/kg or more, about 1 mg/kg or more, about0.95 mg/kg or more, about 0.9 mg/kg or more, about 0.85 mg/kg or more,about 0.8 mg/kg or more, about 0.75 mg/kg or more, about 0.7 mg/kg ormore, about 0.65 mg/kg or more, about 0.6 mg/kg or more, about 0.55mg/kg or more, about 0.5 mg/kg or more, about 0.45 mg/kg or more, about0.4 mg/kg or more, about 0.35 mg/kg or more, about 0.3 mg/kg or more,about 0.25 mg/kg or more, about 0.2 mg/kg or more, about 0.15 mg/kg ormore, about 0.1 mg/kg or more, about 0.09 mg/kg or more, about 0.08mg/kg or more, about 0.07 mg/kg or more, about 0.06 mg/kg or more, about0.05 mg/kg or more, about 0.04 mg/kg or more, about 0.03 mg/kg or more,about 0.02 mg/kg or more, about 0.01 mg/kg or more, about 0.009 mg/kg ormore, about 0.007 mg/kg or more, about 0.005 mg/kg or more, about 0.003mg/kg or more, or about 0.001 mg/kg or more. In all cases, the dosesdescribed herein are less than 10 mg/kg.

In some examples, the effective dose is delivered orally. In someexamples, the effective does is delivered intravenously. In someexamples, the effective does is delivered intravenously by means of anintravenous drip along with saline. In some examples, the effective doesis delivered intravenously by means of an intravenous drip along withother medicines, vitamins, fluids or nutrition. In some examples, theeffective does is delivered subcutaneously. In some examples, theeffective dose is delivered topically. In some examples, the effectivedose is delivered transdermally. In some examples, the effective dose iscombined with other necessary medicines, vitamins, fluids or nutrition.

In some examples, the effective dose is used to treat, prevent oralleviate any of the following diseases or conditions by inducing BDNFwith DNP treatment: Traumatic Brain Injury (TBI), Ischemic stroke,Huntington's disease (Adult-onset Huntington's, Juvenile Huntington'sdisease), Epilepsy (Cluster Seizures, Refractory Seizures, AtypicalAbsence Seizures, Atonic Seizures, Clonic Seizures, myoclonic seizures,tonic seizures, Tonic-Clonic Seizures, Simple Partial Seizures, ComplexPartial Seizures, Secondary Generalized Seizures, Febrile Seizures,Nonepileptic Seizures, Gelastic and Dacrystic Seizures, and AbsenceSeizures), Multiple Sclerosis (MS) (relapse-remitting multiple sclerosis(RRMS), Secondary-progressive MS (SPMS), Primary-progressive MS (PPMS),and Progressive-relapsing MS (PRMS)), Lupus (Systemic LupusErythematosus (SLE), discoid (cutaneous), drug-induced lupus (dil) andneonatal lupus), Diabetes mellitus (Type-1 Diabetes, Type-2 Diabetes,Maturity Onset Diabetes of the Young (MODY: MODY1, MODY2, MODY3, MODY4,MODY5, MODY6, MODY7, MODY8, MODY9, MODY10, MODY11)), Schizophrenia(Paranoid schizophrenia, Disorganized schizophrenia, Catatonicschizophrenia, Residual schizophrenia, Schizoaffective disorder),Myasthenia gravis (MG) (ocular myasthenia gravis, Congenital MG andgeneralized myasthenia gravis), rheumatoid arthritis (RA), Graves'disease, Guillain-Barré syndrome (GBS), Muscular Dystrophy (DuchenneMuscular Dystrophy (DMD), Becker, Myotonic, Congenital, Emery-Dreifuss,Facioscapulohumeral, Limb-girdle, Distal, and Oculopharyngeal), severeburns, aging, Amyotrophic Lateral Sclerosis (ALS), Ataxia (Friedreich'sAtaxia, Spinocerebellar ataxias 1 (SCA1), Spinocerebellar ataxias 2(SCA2), Spinocerebellar ataxias 3 (SCA3), Spinocerebellar ataxias 6(SCA6), Spinocerebellar ataxias 7 (SCAT), Spinocerebellar ataxias 11(SCA11), Dentatorubral pallidolusyian atrophy (DRPLA) and Glutenataxia), Batten Disease or neuronal ceroid lipofuscinoses (NCL)(infantile NCL (INCL), late infantile NCL (LINCL), juvenile NCL (JNCL)or adult NCL (ANCL)), Alzheimer's Disease (Early-onset Alzheimer's,Late-onset Alzheimer's, and Familial Alzheimer's disease (FAD)), Opticneuritis (ON), Leber's hereditary optic neuropathy (LHON), AutismSpectrum Disorders (ASD) (Asperger's Syndrome, Pervasive DevelopmentalDisorders (PDDs), Childhood Disintegrative Disorder (CDD), and Autisticdisorder), Rett syndrome, Angelman's Syndrome, Leigh disease, PraderWilli Syndrome, Fragile-X Syndrome, Depression (Major Depression,Dysthymia, Postpartum Depression, Seasonal Affective Disorder, AtypicalDepression, Psychotic Depression, Bipolar Disorder, PremenstrualDysphoric Disorder, Situational Depression), Parkinson's disease(Idiopathic Parkinson's disease, Vascular parkinsonism, Dementia withLewy bodies, Inherited Parkinson's, Drug-induced Parkinsonism, JuvenileParkinson's and atypical parkinsonism), mitochondrial diseases,developmental disorders, metabolic syndrome (increased blood pressure,high blood sugar level, excess body fat around the waist and abnormalcholesterol levels) and/or autoimmune disorders.

In some examples, the effective dose used to treat, prevent or alleviatethe symptoms of Huntington's disease is 0.005 mg/kg to 1.0 mg/kg. Insome examples, the effective dose used to treat, prevent or alleviateHuntington's disease is 0.01 mg/kg to 0.5 mg/kg. In some examples, theeffective dose used to treat, prevent or alleviate Huntington's diseaseis 0.01 mg/kg to 0.1 mg/kg. In some examples, the effective dose used totreat, prevent or alleviate Huntington's disease is 0.02 mg/kg to 0.1mg/kg. In some examples, the effective dose used to treat, prevent oralleviate Huntington's disease is 0.02 mg/kg to 0.4 mg/kg. In someexamples, the effective dose used to treat, prevent or alleviateHuntington's disease is 0.025 mg/kg to 0.4 mg/kg. In some examples, theeffective dose used to treat, prevent or alleviate Huntington's diseaseis 0.025 mg/kg to 0.08 mg/kg. In some examples, the effective dose usedto treat, prevent or alleviate Huntington's disease is 0.03 mg/kg to0.075 mg/kg. In some examples, the effective dose used to treat, preventor alleviate Huntington's disease is 0.035 mg/kg to 0.4 mg/kg. In someexamples, the effective dose used to treat, prevent or alleviateHuntington's disease is 0.035 mg/kg to 0.1 mg/kg. In some examples, theeffective dose used to treat, prevent or alleviate Huntington's diseaseis 0.035 mg/kg to 0.09 mg/kg. In some examples, the effective dose usedto treat, prevent or alleviate Huntington's disease is 0.035 mg/kg to0.08 mg/kg. In some examples, the effective dose used to treat, preventor alleviate Huntington's disease is 0.035 mg/kg to 0.075 mg/kg. In someexamples, the effective dose used to treat, prevent or alleviateHuntington's disease is 0.045 mg/kg to 0.055 mg/kg. In some examples,the effective dose used to treat, prevent or alleviate Huntington'sdisease is 0.055 mg/kg to 0.085 mg/kg. In some examples, the effectivedose used to treat, prevent or alleviate Huntington's disease is 0.055mg/kg to 0.065 mg/kg. In some examples, the effective dose used totreat, prevent or alleviate Huntington's disease is 0.065 mg/kg to 0.075mg/kg. In some examples, the effective dose used to treat, prevent oralleviate Huntington's disease is 0.075 mg/kg to 0.1 mg/kg. In someexamples, the effective dose used to treat, prevent or alleviateHuntington's disease is 0.07 mg/kg to 0.09 mg/kg. In some examples, theeffective dose used to treat, prevent or alleviate Huntington's diseaseis 0.085 mg/kg to 0.1 mg/kg. In some examples, the effective dose usedto treat, prevent or alleviate Huntington's disease is 0.09 mg/kg to 0.2mg/kg. In some examples, the effective dose used to treat, prevent oralleviate Huntington's disease is 0.1 mg/kg to 0.3 mg/kg. In someexamples, the effective dose used to treat, prevent or alleviateHuntington's disease is 0.2 mg/kg to 0.4 mg/kg.

In some examples, the effective dose used to treat, prevent or alleviatethe symptoms of Huntington's disease is about 0.005 mg/kg to about 1.0mg/kg. In some examples, the effective dose used to treat, prevent oralleviate Huntington's disease is about 0.01 mg/kg to about 0.5 mg/kg.In some examples, the effective dose used to treat, prevent or alleviateHuntington's disease is about 0.01 mg/kg to about 0.1 mg/kg. In someexamples, the effective dose used to treat, prevent or alleviateHuntington's disease is about 0.02 mg/kg to about 0.1 mg/kg. In someexamples, the effective dose used to treat, prevent or alleviateHuntington's disease is about 0.02 mg/kg to about 0.4 mg/kg. In someexamples, the effective dose used to treat, prevent or alleviateHuntington's disease is about 0.025 mg/kg to about 0.4 mg/kg. In someexamples, the effective dose used to treat, prevent or alleviateHuntington's disease is about 0.025 mg/kg to about 0.08 mg/kg. In someexamples, the effective dose used to treat, prevent or alleviateHuntington's disease is about 0.03 mg/kg to about 0.075 mg/kg. In someexamples, the effective dose used to treat, prevent or alleviateHuntington's disease is about 0.035 mg/kg to about 0.4 mg/kg. In someexamples, the effective dose used to treat, prevent or alleviateHuntington's disease is about 0.035 mg/kg to about 0.1 mg/kg. In someexamples, the effective dose used to treat, prevent or alleviateHuntington's disease is about 0.035 mg/kg to about 0.09 mg/kg. In someexamples, the effective dose used to treat, prevent or alleviateHuntington's disease is about 0.035 mg/kg to about 0.08 mg/kg. In someexamples, the effective dose used to treat, prevent or alleviateHuntington's disease is about 0.035 mg/kg to about 0.075 mg/kg. In someexamples, the effective dose used to treat, prevent or alleviateHuntington's disease is about 0.045 mg/kg to about 0.055 mg/kg. In someexamples, the effective dose used to treat, prevent or alleviateHuntington's disease is about 0.055 mg/kg to about 0.085 mg/kg. In someexamples, the effective dose used to treat, prevent or alleviateHuntington's disease is about 0.055 mg/kg to about 0.065 mg/kg. In someexamples, the effective dose used to treat, prevent or alleviateHuntington's disease is about 0.065 mg/kg to about 0.075 mg/kg. In someexamples, the effective dose used to treat, prevent or alleviateHuntington's disease is about 0.075 mg/kg to about 0.1 mg/kg. In someexamples, the effective dose used to treat, prevent or alleviateHuntington's disease is about 0.07 mg/kg to about 0.09 mg/kg. In someexamples, the effective dose used to treat, prevent or alleviateHuntington's disease is about 0.085 mg/kg to about 0.1 mg/kg. In someexamples, the effective dose used to treat, prevent or alleviateHuntington's disease is about 0.09 mg/kg to about 0.2 mg/kg. In someexamples, the effective dose used to treat, prevent or alleviateHuntington's disease is about 0.1 mg/kg to about 0.3 mg/kg. In someexamples, the effective dose used to treat, prevent or alleviateHuntington's disease is about 0.2 mg/kg to about 0.4 mg/kg.

In some examples, the effective dose used to treat, prevent or alleviatethe symptoms of Huntington's disease is 0.001 mg/kg or more. In someexamples, the effective dose used to treat, prevent or alleviate thesymptoms of Huntington's disease is 0.002 mg/kg or more. In someexamples, the effective dose used to treat, prevent or alleviate thesymptoms of Huntington's disease is 0.003 mg/kg or more. In someexamples, the effective dose used to treat, prevent or alleviate thesymptoms of Huntington's disease is 0.004 mg/kg or more. In someexamples, the effective dose used to treat, prevent or alleviate thesymptoms of Huntington's disease is 0.005 mg/kg or more. In someexamples, the effective dose used to treat, prevent or alleviate thesymptoms of Huntington's disease is 0.01 mg/kg or more. In someexamples, the effective dose used to treat, prevent or alleviate thesymptoms of Huntington's disease is 0.025 mg/kg or more. In someexamples, the effective dose used to treat, prevent or alleviate thesymptoms of Huntington's disease is 0.035 mg/kg or more. In someexamples, the effective dose used to treat, prevent or alleviate thesymptoms of Huntington's disease is 0.05 mg/kg or more. In someexamples, the effective dose used to treat, prevent or alleviate thesymptoms of Huntington's disease is 0.075 mg/kg or more. In someexamples, the effective dose used to treat, prevent or alleviate thesymptoms of Huntington's disease is 0.1 mg/kg or more. In some examples,the effective dose used to treat, prevent or alleviate the symptoms ofHuntington's disease is 1 mg/kg or less. In some examples, the effectivedose used to treat, prevent or alleviate the symptoms of Huntington'sdisease is 0.5 mg/kg or less. In some examples, the effective dose usedto treat, prevent or alleviate the symptoms of Huntington's disease is0.35 mg/kg or less. In some examples, the effective dose used to treat,prevent or alleviate the symptoms of Huntington's disease is 0.25 mg/kgor less. In some examples, the effective dose used to treat, prevent oralleviate the symptoms of Huntington's disease is 0.1 mg/kg or less. Insome examples, the effective dose used to treat, prevent or alleviatethe symptoms of Huntington's disease is 0.075 mg/kg or less. In someexamples, the effective dose used to treat, prevent or alleviate thesymptoms of Huntington's disease is 0.05 mg/kg or less. In someexamples, the effective dose used to treat, prevent or alleviate thesymptoms of Huntington's disease is 0.01 mg/kg or less. In all cases,the dose described herein is greater than zero mg/kg and less than 5mg/kg.

In some examples, the effective dose used to treat, prevent or alleviatethe symptoms of Multiple Sclerosis (MS) is 0.01 mg/kg to 5 mg/kg. Insome examples, the effective dose used to treat, prevent or alleviatethe symptoms of Multiple Sclerosis (MS) is 0.01 mg/kg to 1 mg/kg. Insome examples, the effective dose used to treat, prevent or alleviatethe symptoms of Multiple Sclerosis (MS) is 0.05 mg/kg to 5 mg/kg. Insome examples, the effective dose used to treat, prevent or alleviatethe symptoms of Multiple Sclerosis (MS) is 0.05 mg/kg to 1 mg/kg. Insome examples, the effective dose used to treat, prevent or alleviateMultiple Sclerosis (MS) is 0.06 mg/kg to 1 mg/kg. In some examples, theeffective dose used to treat, prevent or alleviate Multiple Sclerosis(MS) is 0.07 mg/kg to 0.9 mg/kg. In some examples, the effective doseused to treat, prevent or alleviate Multiple Sclerosis (MS) is 0.075mg/kg to 0.8 mg/kg. In some examples, the effective dose used to treat,prevent or alleviate Multiple Sclerosis (MS) is 0.07 mg/kg to 0.1 mg/kg.In some examples, the effective dose used to treat, prevent or alleviateMultiple Sclerosis (MS) is 0.08 mg/kg to 0.5 mg/kg. In some examples,the effective dose used to treat, prevent or alleviate MultipleSclerosis (MS) is 0.1 mg/kg to 0.8 mg/kg. In some examples, theeffective dose used to treat, prevent or alleviate Multiple Sclerosis(MS) is 0.3 mg/kg to 0.8 mg/kg. In some examples, the effective doseused to treat, prevent or alleviate Multiple Sclerosis (MS) is 0.4 mg/kgto 0.7 mg/kg. In some examples, the effective dose used to treat,prevent or alleviate Multiple Sclerosis (MS) is 0.7 mg/kg to 0.8 mg/kg.In some examples, the effective dose used to treat, prevent or alleviateMultiple Sclerosis (MS) is 0.8 mg/kg to 1 mg/kg.

In some examples, the effective dose used to treat, prevent or alleviatethe symptoms of Multiple Sclerosis (MS) is about 0.05 mg/kg to about 5mg/kg. In some examples, the effective dose used to treat, prevent oralleviate the symptoms of Multiple Sclerosis (MS) is about 0.01 mg/kg toabout 1 mg/kg. In some examples, the effective dose used to treat,prevent or alleviate the symptoms of Multiple Sclerosis (MS) is about0.05 mg/kg to about 5 mg/kg. In some examples, the effective dose usedto treat, prevent or alleviate the symptoms of Multiple Sclerosis (MS)is about 0.05 mg/kg to about 1 mg/kg. In some examples, the effectivedose used to treat, prevent or alleviate Multiple Sclerosis (MS) isabout 0.06 mg/kg to about 1 mg/kg. In some examples, the effective doseused to treat, prevent or alleviate Multiple Sclerosis (MS) is about0.07 mg/kg to about 0.9 mg/kg. In some examples, the effective dose usedto treat, prevent or alleviate Multiple Sclerosis (MS) is about 0.075mg/kg to about 0.8 mg/kg. In some examples, the effective dose used totreat, prevent or alleviate Multiple Sclerosis (MS) is about 0.07 mg/kgto about 0.1 mg/kg. In some examples, the effective dose used to treat,prevent or alleviate Multiple Sclerosis (MS) is about 0.08 mg/kg toabout 0.5 mg/kg. In some examples, the effective dose used to treat,prevent or alleviate Multiple Sclerosis (MS) is about 0.1 mg/kg to about0.8 mg/kg. In some examples, the effective dose used to treat, preventor alleviate Multiple Sclerosis (MS) is about 0.3 mg/kg to about 0.8mg/kg. In some examples, the effective dose used to treat, prevent oralleviate Multiple Sclerosis (MS) is about 0.4 mg/kg to about 0.7 mg/kg.In some examples, the effective dose used to treat, prevent or alleviateMultiple Sclerosis (MS) is about 0.7 mg/kg to about 0.8 mg/kg. In someexamples, the effective dose used to treat, prevent or alleviateMultiple Sclerosis (MS) is about 0.8 mg/kg to about 1 mg/kg.

In some examples, the effective dose used to treat, prevent or alleviateMultiple Sclerosis (MS) is 1.0 mg/kg or less. In some examples, theeffective dose used to treat, prevent or alleviate Multiple Sclerosis(MS) is 0.9 mg/kg or less. In some examples, the effective dose used totreat, prevent or alleviate Multiple Sclerosis (MS) is 0.8 mg/kg orless. In some examples, the effective dose used to treat, prevent oralleviate Multiple Sclerosis (MS) is 0.7 mg/kg or less. In someexamples, the effective dose used to treat, prevent or alleviateMultiple Sclerosis (MS) is 0.6 mg/kg or less. In some examples, theeffective dose used to treat, prevent or alleviate Multiple Sclerosis(MS) is 0.5 mg/kg or less. In some examples, the effective dose used totreat, prevent or alleviate Multiple Sclerosis (MS) is 0.4 mg/kg orless. In some examples, the effective dose used to treat, prevent oralleviate Multiple Sclerosis (MS) is 0.3 mg/kg or less. In someexamples, the effective dose used to treat, prevent or alleviateMultiple Sclerosis (MS) is 0.2 mg/kg or less. In some examples, theeffective dose used to treat, prevent or alleviate Multiple Sclerosis(MS) is 0.1 mg/kg or less. In some examples, the effective dose used totreat, prevent or alleviate Multiple Sclerosis (MS) is 0.09 mg/kg orless. In some examples, the effective dose used to treat, prevent oralleviate Multiple Sclerosis (MS) is 0.08 mg/kg or less. In someexamples, the effective dose used to treat, prevent or alleviateMultiple Sclerosis (MS) is 0.07 mg/kg or less. In some examples, theeffective dose used to treat, prevent or alleviate Multiple Sclerosis(MS) is 0.05 mg/kg or less. In some examples, the effective dose used totreat, prevent or alleviate Multiple Sclerosis (MS) is 0.01 mg/kg ormore. In some examples, the effective dose used to treat, prevent oralleviate Multiple Sclerosis (MS) is 0.05 mg/kg or more. In someexamples, the effective dose used to treat, prevent or alleviateMultiple Sclerosis (MS) is 0.06 mg/kg or more. In some examples, theeffective dose used to treat, prevent or alleviate Multiple Sclerosis(MS) is 0.07 mg/kg or more. In some examples, the effective dose used totreat, prevent or alleviate Multiple Sclerosis (MS) is 0.08 mg/kg ormore. In some examples, the effective dose used to treat, prevent oralleviate Multiple Sclerosis (MS) is 0.09 mg/kg or more. In someexamples, the effective dose used to treat, prevent or alleviateMultiple Sclerosis (MS) is 0.1 mg/kg or more. In some examples, theeffective dose used to treat, prevent or alleviate Multiple Sclerosis(MS) is 0.15 mg/kg or more. In some examples, the effective dose used totreat, prevent or alleviate Multiple Sclerosis (MS) is 0.2 mg/kg ormore. In some examples, the effective dose used to treat, prevent oralleviate Multiple Sclerosis (MS) is 0.25 mg/kg or more. In someexamples, the effective dose used to treat, prevent or alleviateMultiple Sclerosis (MS) is 0.3 mg/kg or more. In some examples, theeffective dose used to treat, prevent or alleviate Multiple Sclerosis(MS) is 0.35 mg/kg or more. In some examples, the effective dose used totreat, prevent or alleviate Multiple Sclerosis (MS) is 0.4 mg/kg ormore. In some examples, the effective dose used to treat, prevent oralleviate Multiple Sclerosis (MS) is 0.45 mg/kg or more. In someexamples, the effective dose used to treat, prevent or alleviateMultiple Sclerosis (MS) is 0.5 mg/kg or more. In some examples, theeffective dose used to treat, prevent or alleviate Multiple Sclerosis(MS) is 0.55 mg/kg or more. In some examples, the effective dose used totreat, prevent or alleviate Multiple Sclerosis (MS) is 0.6 mg/kg ormore. In some examples, the effective dose used to treat, prevent oralleviate Multiple Sclerosis (MS) is 0.65 mg/kg or more. In someexamples, the effective dose used to treat, prevent or alleviateMultiple Sclerosis (MS) is 0.70 mg/kg or more. In some examples, theeffective dose used to treat, prevent or alleviate Multiple Sclerosis(MS) is 0.75 mg/kg or more. In some examples, the effective dose used totreat, prevent or alleviate Multiple Sclerosis (MS) is 0.8 mg/kg ormore. In some examples, the effective dose used to treat, prevent oralleviate Multiple Sclerosis (MS) is 1.0 mg/kg or more. In all cases,the dose described herein is greater than zero mg/kg and less than 5mg/kg.

In some examples, the effective dose used to treat, prevent or alleviateEpilepsy is 0.05 mg/kg to 1 mg/kg. In some examples, the effective doseused to treat, prevent or alleviate Epilepsy is 0.5 mg/kg to 1 mg/kg. Insome examples, the effective dose used to treat, prevent or alleviateEpilepsy is 0.6 mg/kg to 0.9 mg/kg. In some examples, the effective doseused to treat, prevent or alleviate Epilepsy is 0.7 mg/kg to 0.8 mg/kg.In some examples, the effective dose used to treat, prevent or alleviateEpilepsy is about 0.5 mg/kg to about 1 mg/kg. In some examples, theeffective dose used to treat, prevent or alleviate Epilepsy is about 0.6mg/kg to about 0.9 mg/kg. In some examples, the effective dose used totreat, prevent or alleviate Epilepsy is about 0.7 mg/kg to about 0.8mg/kg. In some examples, the effective dose used to treat, prevent oralleviate Epilepsy is 0.1 mg/kg or more. In some examples, the effectivedose used to treat, prevent or alleviate Epilepsy is 0.4 mg/kg or more.In some examples, the effective dose used to treat, prevent or alleviateEpilepsy is 0.5 mg/kg or more. In some examples, the effective dose usedto treat, prevent or alleviate Epilepsy is 0.6 mg/kg or more. In someexamples, the effective dose used to treat, prevent or alleviateEpilepsy is 0.7 mg/kg or more. In some examples, the effective dose usedto treat, prevent or alleviate Epilepsy is 0.8 mg/kg or more. In someexamples, the effective dose used to treat, prevent or alleviateEpilepsy is 1 mg/kg or less. In some examples, the effective dose usedto treat, prevent or alleviate Epilepsy is 0.9 mg/kg or less. In someexamples, the effective dose used to treat, prevent or alleviateEpilepsy is 0.8 mg/kg or less. In some examples, the effective dose usedto treat, prevent or alleviate Epilepsy is 0.7 mg/kg or less. In someexamples, the effective dose used to treat, prevent or alleviateEpilepsy is 0.5 mg/kg or less. In all cases, the dose described hereinis greater than zero mg/kg and less than 5 mg/kg.

In some examples, the effective dose used to treat, prevent or alleviatethe symptoms of Rett Syndrome is 0.005 mg/kg to 1 mg/kg. In someexamples, the effective dose used to treat, prevent or alleviate RettSyndrome is 0.02 mg/kg to 1 mg/kg. In some examples, the effective doseused to treat, prevent or alleviate Rett Syndrome is 0.01 mg/kg to 0.5mg/kg. In some examples, the effective dose used to treat, prevent oralleviate Rett Syndrome is 0.02 mg/kg to 0.4 mg/kg. In some examples,the effective dose used to treat, prevent or alleviate Rett Syndrome is0.025 mg/kg to 0.4 mg/kg. In some examples, the effective dose used totreat, prevent or alleviate Rett Syndrome is 0.025 mg/kg to 0.08 mg/kg.In some examples, the effective dose used to treat, prevent or alleviateRett Syndrome is 0.03 mg/kg to 0.075 mg/kg. In some examples, theeffective dose used to treat, prevent or alleviate Rett Syndrome is0.035 mg/kg to 0.4 mg/kg. In some examples, the effective dose used totreat, prevent or alleviate Rett Syndrome is 0.035 mg/kg to 0.1 mg/kg.In some examples, the effective dose used to treat, prevent or alleviateRett Syndrome is 0.035 mg/kg to 0.09 mg/kg. In some examples, theeffective dose used to treat, prevent or alleviate Rett Syndrome is0.035 mg/kg to 0.08 mg/kg. In some examples, the effective dose used totreat, prevent or alleviate Rett Syndrome is 0.035 mg/kg to 0.075 mg/kg.In some examples, the effective dose used to treat, prevent or alleviateRett Syndrome is 0.045 mg/kg to 0.055 mg/kg. In some examples, theeffective dose used to treat, prevent or alleviate Rett Syndrome is0.055 mg/kg to 0.085 mg/kg. In some examples, the effective dose used totreat, prevent or alleviate Rett Syndrome is 0.055 mg/kg to 0.065 mg/kg.In some examples, the effective dose used to treat, prevent or alleviateRett Syndrome is 0.065 mg/kg to 0.075 mg/kg. In some examples, theeffective dose used to treat, prevent or alleviate Rett Syndrome is0.075 mg/kg to 0.1 mg/kg. In some examples, the effective dose used totreat, prevent or alleviate Rett Syndrome is 0.07 mg/kg to 0.09 mg/kg.In some examples, the effective dose used to treat, prevent or alleviateRett Syndrome is 0.085 mg/kg to 0.1 mg/kg. In some examples, theeffective dose used to treat, prevent or alleviate Rett Syndrome is 0.09mg/kg to 0.2 mg/kg.

In some examples, the effective dose used to treat, prevent or alleviatethe symptoms of Rett Syndrome is about 0.005 mg/kg to about 1.0 mg/kg.In some examples, the effective dose used to treat, prevent or alleviateRett Syndrome is about 0.02 mg/kg to about 1 mg/kg. In some examples,the effective dose used to treat, prevent or alleviate Rett Syndrome isabout 0.01 mg/kg to about 0.5 mg/kg. In some examples, the effectivedose used to treat, prevent or alleviate Rett Syndrome is about 0.02mg/kg to about 0.4 mg/kg. In some examples, the effective dose used totreat, prevent or alleviate Rett Syndrome is about 0.025 mg/kg to about0.4 mg/kg. In some examples, the effective dose used to treat, preventor alleviate Rett Syndrome is about 0.025 mg/kg to about 0.08 mg/kg. Insome examples, the effective dose used to treat, prevent or alleviateRett Syndrome is about 0.03 mg/kg to about 0.075 mg/kg. In someexamples, the effective dose used to treat, prevent or alleviate RettSyndrome is about 0.035 mg/kg to about 0.4 mg/kg. In some examples, theeffective dose used to treat, prevent or alleviate Rett Syndrome isabout 0.035 mg/kg to about 0.1 mg/kg. In some examples, the effectivedose used to treat, prevent or alleviate Rett Syndrome is about 0.035mg/kg to about 0.09 mg/kg. In some examples, the effective dose used totreat, prevent or alleviate Rett Syndrome is about 0.035 mg/kg to about0.08 mg/kg. In some examples, the effective dose used to treat, preventor alleviate Rett Syndrome is about 0.035 mg/kg to about 0.075 mg/kg. Insome examples, the effective dose used to treat, prevent or alleviateRett Syndrome is about 0.045 mg/kg to about 0.055 mg/kg. In someexamples, the effective dose used to treat, prevent or alleviate RettSyndrome is about 0.055 mg/kg to about 0.085 mg/kg. In some examples,the effective dose used to treat, prevent or alleviate Rett Syndrome isabout 0.055 mg/kg to about 0.065 mg/kg. In some examples, the effectivedose used to treat, prevent or alleviate Rett Syndrome is about 0.065mg/kg to about 0.075 mg/kg. In some examples, the effective dose used totreat, prevent or alleviate Rett Syndrome is about 0.075 mg/kg to about0.1 mg/kg. In some examples, the effective dose used to treat, preventor alleviate Rett Syndrome is about 0.07 mg/kg to about 0.09 mg/kg. Insome examples, the effective dose used to treat, prevent or alleviateRett Syndrome is about 0.085 mg/kg to about 0.1 mg/kg. In some examples,the effective dose used to treat, prevent or alleviate Rett Syndrome isabout 0.09 mg/kg to about 0.2 mg/kg.

In some examples, the effective dose used to treat, prevent or alleviatethe symptoms of Rett Syndrome is 0.01 mg/kg or more. In some examples,the effective dose used to treat, prevent or alleviate the symptoms ofRett Syndrome is 0.02 mg/kg or more. In some examples, the effectivedose used to treat, prevent or alleviate the symptoms of Rett Syndromeis 0.03 mg/kg or more. In some examples, the effective dose used totreat, prevent or alleviate the symptoms of Rett Syndrome is 0.04 mg/kgor more. In some examples, the effective dose used to treat, prevent oralleviate the symptoms of Rett Syndrome is 0.05 mg/kg or more. In someexamples, the effective dose used to treat, prevent or alleviate thesymptoms of Rett Syndrome is 0.06 mg/kg or more. In some examples, theeffective dose used to treat, prevent or alleviate the symptoms of RettSyndrome is 0.07 mg/kg or more. In some examples, the effective doseused to treat, prevent or alleviate the symptoms of Rett Syndrome is0.08 mg/kg or more. In some examples, the effective dose used to treat,prevent or alleviate the symptoms of Rett Syndrome is 0.09 mg/kg ormore. In some examples, the effective dose used to treat, prevent oralleviate the symptoms of Rett Syndrome is 0.5 mg/kg or less. In someexamples, the effective dose used to treat, prevent or alleviate thesymptoms of Rett Syndrome is 0.3 mg/kg or less. In some examples, theeffective dose used to treat, prevent or alleviate the symptoms of RettSyndrome is 0.1 mg/kg or less. In some examples, the effective dose usedto treat, prevent or alleviate the symptoms of Rett Syndrome is 0.075mg/kg or less. In some examples, the effective dose used to treat,prevent or alleviate the symptoms of Rett Syndrome is 0.05 mg/kg orless. In some examples, the effective dose used to treat, prevent oralleviate the symptoms of Rett Syndrome is 0.01 mg/kg or less. In allcases, the dose described herein is greater than zero mg/kg and lessthan 5 mg/kg.

In some examples, the effective dose used to treat, prevent or alleviatethe symptoms of Parkinson's Disease is 0.01 mg/kg to 1 mg/kg. In someexamples, the effective dose used to treat, prevent or alleviate thesymptoms of Parkinson's Disease is 0.01 mg/kg to 0.5 mg/kg. In someexamples, the effective dose used to treat, prevent or alleviate thesymptoms of Parkinson's Disease is 0.05 mg/kg to 0.5 mg/kg. In someexamples, the effective dose used to treat, prevent or alleviateParkinson's Disease is 0.05 mg/kg to 0.1 mg/kg. In some examples, theeffective dose used to treat, prevent or alleviate Parkinson's Diseaseis 0.06 mg/kg to 0.5 mg/kg. In some examples, the effective dose used totreat, prevent or alleviate Parkinson's Disease is 0.07 mg/kg to 0.4mg/kg. In some examples, the effective dose used to treat, prevent oralleviate Parkinson's Disease is 0.08 mg/kg to 0.4 mg/kg. In someexamples, the effective dose used to treat, prevent or alleviateParkinson's Disease is 0.09 mg/kg to 0.4 mg/kg. In some examples, theeffective dose used to treat, prevent or alleviate Parkinson's Diseaseis 0.075 mg/kg to 0.1 mg/kg. In some examples, the effective dose usedto treat, prevent or alleviate Parkinson's Disease is 0.09 mg/kg to 0.2mg/kg. In some examples, the effective dose used to treat, prevent oralleviate Parkinson's Disease is 0.1 mg/kg to 0.4 mg/kg. In someexamples, the effective dose used to treat, prevent or alleviateParkinson's Disease is 0.2 mg/kg to 0.5 mg/kg.

In some examples, the effective dose used to treat, prevent or alleviatethe symptoms of Parkinson's Disease is about 0.01 mg/kg to about 1mg/kg. In some examples, the effective dose used to treat, prevent oralleviate the symptoms of Parkinson's Disease is about 0.01 mg/kg toabout 0.5 mg/kg. In some examples, the effective dose used to treat,prevent or alleviate the symptoms of Parkinson's Disease is about 0.05mg/kg to about 0.5 mg/kg. In some examples, the effective dose used totreat, prevent or alleviate Parkinson's Disease is about 0.05 mg/kg toabout 0.1 mg/kg. In some examples, the effective dose used to treat,prevent or alleviate Parkinson's Disease is about 0.06 mg/kg to about0.5 mg/kg. In some examples, the effective dose used to treat, preventor alleviate Parkinson's Disease is about 0.07 mg/kg to about 0.4 mg/kg.In some examples, the effective dose used to treat, prevent or alleviateParkinson's Disease is about 0.08 mg/kg to about 0.4 mg/kg. In someexamples, the effective dose used to treat, prevent or alleviateParkinson's Disease is about 0.09 mg/kg to about 0.4 mg/kg. In someexamples, the effective dose used to treat, prevent or alleviateParkinson's Disease is about 0.075 mg/kg to about 0.1 mg/kg. In someexamples, the effective dose used to treat, prevent or alleviateParkinson's Disease is about 0.09 mg/kg to about 0.2 mg/kg. In someexamples, the effective dose used to treat, prevent or alleviateParkinson's Disease is about 0.1 mg/kg to about 0.4 mg/kg. In someexamples, the effective dose used to treat, prevent or alleviateParkinson's Disease is about 0.2 mg/kg to about 0.5 mg/kg.

In some examples, the effective dose used to treat, prevent or alleviateParkinson's Disease is 1.0 mg/kg or less. In some examples, theeffective dose used to treat, prevent or alleviate Parkinson's Diseaseis 0.5 mg/kg or less. In some examples, the effective dose used totreat, prevent or alleviate Parkinson's Disease is 0.4 mg/kg or less. Insome examples, the effective dose used to treat, prevent or alleviateParkinson's Disease is 0.3 mg/kg or less. In some examples, theeffective dose used to treat, prevent or alleviate Parkinson's Diseaseis 0.2 mg/kg or less. In some examples, the effective dose used totreat, prevent or alleviate Parkinson's Disease is 0.1 mg/kg or less. Insome examples, the effective dose used to treat, prevent or alleviateParkinson's Disease is 0.09 mg/kg or less. In some examples, theeffective dose used to treat, prevent or alleviate Parkinson's Diseaseis 0.08 mg/kg or less. In some examples, the effective dose used totreat, prevent or alleviate Parkinson's Disease is 0.07 mg/kg or less.In some examples, the effective dose used to treat, prevent or alleviateParkinson's Disease is 0.05 mg/kg or less. In some examples, theeffective dose used to treat, prevent or alleviate Parkinson's Diseaseis 0.01 mg/kg or more. In some examples, the effective dose used totreat, prevent or alleviate Parkinson's Disease is 0.05 mg/kg or more.In some examples, the effective dose used to treat, prevent or alleviateParkinson's Disease is 0.06 mg/kg or more. In some examples, theeffective dose used to treat, prevent or alleviate Parkinson's Diseaseis 0.07 mg/kg or more. In some examples, the effective dose used totreat, prevent or alleviate Parkinson's Disease is 0.08 mg/kg or more.In some examples, the effective dose used to treat, prevent or alleviateParkinson's Disease is 0.09 mg/kg or more. In some examples, theeffective dose used to treat, prevent or alleviate Parkinson's Diseaseis 0.1 mg/kg or more. In some examples, the effective dose used totreat, prevent or alleviate Parkinson's Disease is 0.15 mg/kg or more.In some examples, the effective dose used to treat, prevent or alleviateParkinson's Disease is 0.2 mg/kg or more. In some examples, theeffective dose used to treat, prevent or alleviate Parkinson's Diseaseis 0.25 mg/kg or more. In some examples, the effective dose used totreat, prevent or alleviate Parkinson's Disease is 0.3 mg/kg or more. Insome examples, the effective dose used to treat, prevent or alleviateMultiple Sclerosis (MS) is 0.35 mg/kg or more. In some examples, theeffective dose used to treat, prevent or alleviate Parkinson's Diseaseis 0.4 mg/kg or more. In some examples, the effective dose used totreat, prevent or alleviate Parkinson's Disease is 0.45 mg/kg or more.In some examples, the effective dose used to treat, prevent or alleviateParkinson's Disease is 0.5 mg/kg or more. In all cases, the dosedescribed herein is greater than zero mg/kg and less than 5 mg/kg.

In some examples, the effective dose used to treat, prevent or alleviatethe symptoms of Alzheimer's is 0.005 mg/kg to 1.0 mg/kg. In someexamples, the effective dose used to treat, prevent or alleviateAlzheimer's is 0.01 mg/kg to 0.5 mg/kg. In some examples, the effectivedose used to treat, prevent or alleviate Alzheimer's is 0.02 mg/kg to0.4 mg/kg. In some examples, the effective dose used to treat, preventor alleviate Alzheimer's is 0.025 mg/kg to 0.4 mg/kg. In some examples,the effective dose used to treat, prevent or alleviate Alzheimer's is0.025 mg/kg to 0.08 mg/kg. In some examples, the effective dose used totreat, prevent or alleviate Alzheimer's is 0.03 mg/kg to 0.075 mg/kg. Insome examples, the effective dose used to treat, prevent or alleviateAlzheimer's is 0.035 mg/kg to 0.4 mg/kg. In some examples, the effectivedose used to treat, prevent or alleviate Alzheimer's is 0.035 mg/kg to0.1 mg/kg. In some examples, the effective dose used to treat, preventor alleviate Alzheimer's is 0.035 mg/kg to 0.09 mg/kg. In some examples,the effective dose used to treat, prevent or alleviate Alzheimer's is0.035 mg/kg to 0.08 mg/kg. In some examples, the effective dose used totreat, prevent or alleviate Alzheimer's is 0.035 mg/kg to 0.075 mg/kg.In some examples, the effective dose used to treat, prevent or alleviateAlzheimer's is 0.045 mg/kg to 0.055 mg/kg. In some examples, theeffective dose used to treat, prevent or alleviate Alzheimer's is 0.055mg/kg to 0.085 mg/kg. In some examples, the effective dose used totreat, prevent or alleviate Alzheimer's is 0.055 mg/kg to 0.065 mg/kg.In some examples, the effective dose used to treat, prevent or alleviateAlzheimer's is 0.065 mg/kg to 0.075 mg/kg. In some examples, theeffective dose used to treat, prevent or alleviate Alzheimer's is 0.075mg/kg to 0.1 mg/kg. In some examples, the effective dose used to treat,prevent or alleviate Alzheimer's is 0.07 mg/kg to 0.09 mg/kg. In someexamples, the effective dose used to treat, prevent or alleviateAlzheimer's is 0.085 mg/kg to 0.1 mg/kg. In some examples, the effectivedose used to treat, prevent or alleviate Alzheimer's is 0.09 mg/kg to0.2 mg/kg. In some examples, the effective dose used to treat, preventor alleviate Alzheimer's is 0.1 mg/kg to 0.3 mg/kg. In some examples,the effective dose used to treat, prevent or alleviate Alzheimer's is0.2 mg/kg to 0.4 mg/kg.

In some examples, the effective dose used to treat, prevent or alleviatethe symptoms of Alzheimer's is about 0.005 mg/kg to about 1.0 mg/kg. Insome examples, the effective dose used to treat, prevent or alleviateAlzheimer's is about 0.01 mg/kg to about 0.5 mg/kg. In some examples,the effective dose used to treat, prevent or alleviate Alzheimer's isabout 0.02 mg/kg to about 0.4 mg/kg. In some examples, the effectivedose used to treat, prevent or alleviate Alzheimer's is about 0.025mg/kg to about 0.4 mg/kg. In some examples, the effective dose used totreat, prevent or alleviate Alzheimer's is about 0.025 mg/kg to about0.08 mg/kg. In some examples, the effective dose used to treat, preventor alleviate Alzheimer's is about 0.03 mg/kg to about 0.075 mg/kg. Insome examples, the effective dose used to treat, prevent or alleviateAlzheimer's is about 0.035 mg/kg to about 0.4 mg/kg. In some examples,the effective dose used to treat, prevent or alleviate Alzheimer's isabout 0.035 mg/kg to about 0.1 mg/kg. In some examples, the effectivedose used to treat, prevent or alleviate Alzheimer's is about 0.035mg/kg to about 0.09 mg/kg. In some examples, the effective dose used totreat, prevent or alleviate Alzheimer's is about 0.035 mg/kg to about0.08 mg/kg. In some examples, the effective dose used to treat, preventor alleviate Alzheimer's is about 0.035 mg/kg to about 0.075 mg/kg. Insome examples, the effective dose used to treat, prevent or alleviateAlzheimer's is about 0.045 mg/kg to about 0.055 mg/kg. In some examples,the effective dose used to treat, prevent or alleviate Alzheimer's isabout 0.055 mg/kg to about 0.085 mg/kg. In some examples, the effectivedose used to treat, prevent or alleviate Alzheimer's is about 0.055mg/kg to about 0.065 mg/kg. In some examples, the effective dose used totreat, prevent or alleviate Alzheimer's is about 0.065 mg/kg to about0.075 mg/kg. In some examples, the effective dose used to treat, preventor alleviate Alzheimer's is about 0.075 mg/kg to about 0.1 mg/kg. Insome examples, the effective dose used to treat, prevent or alleviateAlzheimer's is about 0.07 mg/kg to about 0.09 mg/kg. In some examples,the effective dose used to treat, prevent or alleviate Alzheimer's isabout 0.085 mg/kg to about 0.1 mg/kg. In some examples, the effectivedose used to treat, prevent or alleviate Alzheimer's is about 0.09 mg/kgto about 0.2 mg/kg. In some examples, the effective dose used to treat,prevent or alleviate Alzheimer's is about 0.1 mg/kg to about 0.3 mg/kg.In some examples, the effective dose used to treat, prevent or alleviateAlzheimer's is about 0.2 mg/kg to about 0.4 mg/kg.

In some examples, the effective dose used to treat, prevent or alleviatethe symptoms of Alzheimer's is 0.001 mg/kg or more. In some examples,the effective dose used to treat, prevent or alleviate the symptoms ofAlzheimer's is 0.002 mg/kg or more. In some examples, the effective doseused to treat, prevent or alleviate the symptoms of Alzheimer's is 0.003mg/kg or more. In some examples, the effective dose used to treat,prevent or alleviate the symptoms of Alzheimer's is 0.004 mg/kg or more.In some examples, the effective dose used to treat, prevent or alleviatethe symptoms of Alzheimer's is 0.005 mg/kg or more. In some examples,the effective dose used to treat, prevent or alleviate the symptoms ofAlzheimer's is 0.01 mg/kg or more. In some examples, the effective doseused to treat, prevent or alleviate the symptoms of Alzheimer's is 0.025mg/kg or more. In some examples, the effective dose used to treat,prevent or alleviate the symptoms of Alzheimer's is 0.035 mg/kg or more.In some examples, the effective dose used to treat, prevent or alleviatethe symptoms of Alzheimer's is 0.05 mg/kg or more. In some examples, theeffective dose used to treat, prevent or alleviate the symptoms ofAlzheimer's is 0.075 mg/kg or more. In some examples, the effective doseused to treat, prevent or alleviate the symptoms of Alzheimer's is 0.1mg/kg or more. In some examples, the effective dose used to treat,prevent or alleviate the symptoms of Alzheimer's is 0.5 mg/kg or less.In some examples, the effective dose used to treat, prevent or alleviatethe symptoms of Alzheimer's is 0.35 mg/kg or less. In some examples, theeffective dose used to treat, prevent or alleviate the symptoms ofAlzheimer's is 0.25 mg/kg or less. In some examples, the effective doseused to treat, prevent or alleviate the symptoms of Alzheimer's is 0.1mg/kg or less. In some examples, the effective dose used to treat,prevent or alleviate the symptoms of Alzheimer's is 0.075 mg/kg or less.In some examples, the effective dose used to treat, prevent or alleviatethe symptoms of Alzheimer's is 0.05 mg/kg or less. In all cases, thedose described herein is greater than zero mg/kg and less than 5 mg/kg.

In some examples, the invention is a method of treating any of thesediseases, or of treating neuromuscular, neurodegenerative, autoimmune,developmental, metabolic, or any disorder related to aging, comprisingadministering to a patient in need of treatment of a traumatic CNSinjury or neurodegenerative disease an effective dose of DNP, or apharmaceutically acceptable salt thereof, over a period sufficientlylong to achieve remission of the symptoms of the disease, wherein theeffective dose of the DNP is continued in the dose range of 0.001 mg/kgof body weight to 5 mg/kg of body weight to induce BDNF expression inbrain. Indeed, the invention comprises administration of DNP, whereinthe dose of DNP is useful to prevent harm in humans, as a means to avoidinducing too much BDNF, or have no effect by inducing too little BDNF.As is also apparent from the disclosures herein, the invention alsocomprises enhancing expression of BDNF, which provides protection frommuscle wasting or muscle dysfunction, since BDNF is expressed not onlyin brain, but in muscle and may act as a myokine.

In some examples, the invention is a method of treating neuromuscular orneurodegenerative or autoimmune or developmental or metabolic disorders,comprising receiving an effective dose of DNP, or a pharmaceuticallyacceptable salt thereof, over period sufficiently long to achieveremission of the symptoms of the disease, wherein the effective dose ofthe DNP is continued to be received in the dose range of 0.001 mg/kg ofbody weight to 5 mg/kg of body weight to increase BDNF to attenuatedisease progression or provide remission of symptoms. In some examples,the invention is a method of treating neuromuscular or neurodegenerativeor autoimmune or developmental or metabolic disorders, comprisingproviding instructions to administer an effective dose DNP, or apharmaceutically acceptable salt thereof, over period sufficiently longto achieve remission of the symptoms of the disease, wherein theeffective dose of the DNP is instructed to be received in the dose rangeof 0.001 mg/kg of body weight to 5 mg/kg of body weight.

In some examples, the invention is a method of treating any of thediseases identified herein, whereby the effective dose of DNP has alasting effect on sustaining elevated levels of BDNF for up to threeweeks after the last dose of DNP is received. In some examples, theinvention is a method of treating any of the diseases identified herein,whereby the effective dose of DNP has a lasting effect on sustainingelevated levels of BDNF for up to two weeks after the last dose of DNPis received. In some examples, the invention is a method of treating anyof the diseases identified herein, whereby the effective dose of DNP hasa lasting effect on sustaining elevated levels of BDNF for up to oneweek after the last dose of DNP is received. In some examples, theinvention is a method of treating any of the diseases identified herein,whereby the effective dose of DNP has a lasting effect on sustainingelevated levels of BDNF for up to three days after the last dose of DNPis received. In some examples, the invention is a method of treating anyof the diseases identified herein, whereby the effective dose of DNP hasa lasting effect on sustaining elevated levels of BDNF for up to twodays after the last dose of DNP is received. In some examples, theinvention is a method of treating any of the diseases identified herein,whereby the effective dose of DNP has a lasting effect on sustainingelevated levels of BDNF for up to one day after the last dose of DNP isreceived.

In an embodiment, a dose encompassed herein may be administered as acomposition based on the weight of the subject. In an embodiment, a dosemay be administered per unit weight of the subject (e.g., mg of acomposition described herein per kg weight of subject). In anembodiment, a dose encompassed herein may be administered as acomposition based solely on the weight of the dose, without regard tothe weight of the subject (e.g., mg of a composition described hereinper dose administered to subject). In an embodiment, the dose isdetermined based on the weight of the active ingredients in the carrier.In another embodiment, the dose is determined based on the total weightof the active ingredients of the composition in the carrier. We arepresuming in our dose range, that the average adult patient weightsapproximately 60 kg.

Composition

In some embodiments, a pharmaceutical composition includes DNP, or apharmaceutically acceptable salt, solvate, or hydrate thereof,comprising an effective dose of DNP, wherein the effective dose of theDNP is in the range of 0.001 mg/kg of body weight to 5 mg/kg of bodyweight; 0.01 mg/kg to 1 mg/kg; 0.01 mg/kg to 0.1 mg/kg; 0.1 mg/kg to 0.5mg/kg; or 1 mg/kg to 5 mg/kg. In some embodiments, the pharmaceuticalcomposition is an effective dose to induce BDNF expression to reverse,slow or prevent neuromuscular and/or neurodegeneration and/or musclewasting.

In some embodiments, a pharmaceutical composition includes DNP, or apharmaceutically acceptable salt, solvate, or hydrate thereof,comprising an effective dose of DNP, wherein the effective dose of theDNP is in the range of about 0.001 mg/kg of body weight to about 5 mg/kgof body weight; about 0.01 mg/kg to about 1 mg/kg; about 0.01 mg/kg toabout 0.1 mg/kg; about 0.1 mg/kg; about 0.1 mg/kg to about 0.5 mg/kg;about 0.5 mg/kg; about 1 mg/kg; about 1 mg/kg to about 5 mg/kg; about 5mg/kg. In some embodiments, the pharmaceutical composition is aneffective dose to induce BDNF expression to reverse, slow or preventneuromuscular and/or neurodegeneration and/or muscle wasting.

In some embodiments, the pharmaceutical composition is an immediaterelease formation. In some embodiments, the pharmaceutical compositionis rapidly dissolving. In some embodiments, the pharmaceuticalcomposition is a sustained release formation. In some embodiments, thepharmaceutical composition is a controlled release formation.

In other embodiments, as set forth in greater detail elsewhere herein,the dosage and dosing regimen for the active ingredients may beoptimized based on the health and condition of the subject to betreated, as well as the desired outcome of the treatment.

Unit Dose

In some embodiments, a pharmaceutical composition includes DNP, or apharmaceutically acceptable salt, solvate, or hydrate thereof,comprising a unit dose, wherein the unit dose is in the range of about0.1 mg to about 300 mg; wherein the unit dose is in the range of about0.1 mg to about 1 mg; wherein the unit dose is in the range of about 1mg to about 5 mg; wherein the unit dose is about 1 mg; wherein the unitdose is about 2 mg; wherein the unit dose is about 3 mg; wherein theunit dose is about 4 mg; wherein the unit dose is about 5 mg; whereinthe unit dose is the range of about 5 mg to about 10 mg; wherein theunit dose is about 6 mg; wherein the unit dose is about 7 mg; whereinthe unit dose is about 8 mg; wherein the unit dose is about 9 mg;wherein the unit dose is about 10 mg; wherein the unit dose is the rangeof about 10 mg to about 15 mg; wherein the unit dose is about 11 mg;wherein the unit dose is about 12 mg; wherein the unit dose is about 13mg; wherein the unit dose is about 14 mg; wherein the unit dose is about15 mg; wherein the unit dose is the range of about 15 mg to about 20 mg;wherein the unit dose is about 16 mg; wherein the unit dose is about 17mg; wherein the unit dose is about 18 mg; wherein the unit dose is about19 mg; wherein the unit dose is about 20 mg; wherein the unit dose isthe range of about 20 mg to about 30 mg; wherein the unit dose is about25 mg; wherein the unit dose is about 30 mg; wherein the unit dose isthe range of about 30 mg to about 40 mg; wherein the unit dose is about35 mg; wherein the unit dose is about 40 mg; wherein the unit dose isthe range of about 40 mg to about 50 mg; wherein the unit dose is about45 mg; wherein the unit dose is about 50 mg; wherein the unit dose isthe range of about 50 mg to about 100 mg; wherein the unit dose is about75 mg; wherein the unit dose is about 100 mg; wherein the unit dose isthe range of about 100 mg to about 200 mg; wherein the unit dose isabout 150 mg; wherein the unit dose is about 200 mg; wherein the unitdose is the range of about 200 mg to about 300 mg; wherein the unit doseis about 200 mg; wherein the unit dose is about 250 mg; or wherein theunit dose is about 300 mg.

In some embodiments, a pharmaceutical composition includes DNP, or apharmaceutically acceptable salt, solvate, or hydrate thereof,comprising a unit dose, wherein the unit dose is in the range of 0.1 mgto 300 mg; wherein the unit dose is in the range of 0.1 mg to 1 mg;wherein the unit dose is in the range of 1 mg to 5 mg; wherein the unitdose is 1 mg; wherein the unit dose is 2 mg; wherein the unit dose is 3mg; wherein the unit dose is 4 mg; wherein the unit dose is 5 mg;wherein the unit dose is the range of 5 mg to 10 mg; wherein the unitdose is 6 mg; wherein the unit dose is 7 mg; wherein the unit dose is 8mg; wherein the unit dose is 9 mg; wherein the unit dose is 10 mg;wherein the unit dose is the range of 10 mg to 15 mg; wherein the unitdose is 11 mg; wherein the unit dose is 12 mg; wherein the unit dose is13 mg; wherein the unit dose is 14 mg; wherein the unit dose is 15 mg;wherein the unit dose is the range of 15 mg to 20 mg; wherein the unitdose is 16 mg; wherein the unit dose is 17 mg; wherein the unit dose is18 mg; wherein the unit dose is 19 mg; wherein the unit dose is 20 mg;wherein the unit dose is the range of 20 mg to 30 mg; wherein the unitdose is 25 mg; wherein the unit dose is 30 mg; wherein the unit dose isthe range of 30 mg to 40 mg; wherein the unit dose is 35 mg; wherein theunit dose is 40 mg; wherein the unit dose is the range of 40 mg to 50mg; wherein the unit dose is 45 mg; wherein the unit dose is 50 mg;wherein the unit dose is the range of 50 mg to 100 mg; wherein the unitdose is 75 mg; wherein the unit dose is 100 mg; wherein the unit dose isthe range of 100 mg to 200 mg; wherein the unit dose is 150 mg; whereinthe unit dose is 200 mg; wherein the unit dose is the range of 200 mg to300 mg; wherein the unit dose is 200 mg; wherein the unit dose is 250mg; or wherein the unit dose is 300 mg.

In some embodiments, a pharmaceutical composition includes DNP, or apharmaceutically acceptable salt, solvate, or hydrate thereof,comprising a unit dose, wherein the unit dose is in the range of 0.1 mgor more; wherein the unit dose is in the range of 0.5 mg or more;wherein the unit dose is in the range of 1 mg or more; wherein the unitdose is 5 mg or more; wherein the unit dose is 10 mg or more; whereinthe unit dose is 15 mg or more; wherein the unit dose is 20 mg or more;wherein the unit dose is 30 mg or more; wherein the unit dose is 40 mgor more; wherein the unit dose is 50 mg or more; wherein the unit doseis 100 mg or more; wherein the unit dose is 150 mg or more; wherein theunit dose is 200 mg or more; or wherein the unit dose is 250 mg or more,but in all cases not greater than 300 mg.

In some embodiments, a pharmaceutical composition includes DNP, or apharmaceutically acceptable salt, solvate, or hydrate thereof,comprising a unit dose, wherein the unit dose is 0.25 mg or less, but inall cases greater than zero; wherein the unit dose is 0.5 mg or less;wherein the unit dose is 1 mg or less; wherein the unit dose is 5 mg orless; wherein the unit dose is 10 mg or less; wherein the unit dose is15 mg or less; wherein the unit dose is 20 mg or less; wherein the unitdose is 30 mg or less; wherein the unit dose is 40 mg or less; whereinthe unit dose is 50 mg or less; wherein the unit dose is 100 mg or less;wherein the unit dose is 150 mg or less; wherein the unit dose is 200 mgor less; wherein the unit dose is 250 mg or less; or wherein the unitdose is 300 mg or less.

In some embodiments, the unit dose is an immediate release formation. Insome embodiments, the unit dose is an extended release formation. Insome embodiments, the unit dose is a sustained release formation. Insome embodiments, the unit dose is a controlled release formation. Insome embodiments, the unit dose is an oral dosage form. In someembodiments, the oral dosage form is a tablet. In some embodiments, theoral dosage form is a capsule. In some embodiments, the unit dose is acapsule with no filler. In some embodiments, the oral dosage form israpidly dissolving.

In some embodiments, the unit dose is delivered intravenously. In someembodiments, the unit dose is delivered by means of an intravenous dripalong with saline. In some embodiments, the unit dose is delivered bymeans of an intravenous drip along with saline, other medications,vitamins and/or nourishment. In some embodiments, the unit dose isdelivered subcutaneously. In some embodiments, the unit dose isdelivered topically. In some embodiments, the unit dose is deliveredtransdermally. In some embodiments, the unit dose is in the form of apatch.

In some embodiments, the unit dose is an effective amount to induce BDNFexpression to reverse, slow or prevent neuromuscular and/orneurodegeneration and/or muscle wasting. In some embodiments, the unitdose is a treatment for Huntington's disease. In some embodiments, theunit dose is a treatment for Multiple Sclerosis (MS). In someembodiments, the unit dose is a treatment for Epilepsy. In someembodiments, the unit dose is a treatment for Parkinson's Disease. Insome embodiments, the unit dose is a treatment for Alzheimer's. In someembodiments, the unit dose is a treatment for Rhett Syndrome. In someembodiments, the unit dose is a treatment for, but not limited to,Traumatic Brain Injury (TBI), Ischemic stroke, Huntington's disease(Adult-onset Huntington's, Juvenile Huntington's disease), Epilepsy(Cluster Seizures, Refractory Seizures, Atypical Absence Seizures,Atonic Seizures, Clonic Seizures, myoclonic seizures, tonic seizures,Tonic-Clonic Seizures, Simple Partial Seizures, Complex PartialSeizures, Secondary Generalized Seizures, Febrile Seizures, NonepilepticSeizures, Gelastic and Dacrystic Seizures, and Absence Seizures),Multiple Sclerosis (MS) (relapse-remitting multiple sclerosis (RRMS),Secondary-progressive MS (SPMS), Primary-progressive MS (PPMS), andProgressive-relapsing MS (PRMS)), Lupus (Systemic Lupus Erythematosus(SLE), discoid (cutaneous), drug-induced lupus (dil) and neonatallupus), Diabetes mellitus (Type-1 Diabetes, Type-2 Diabetes, Maturityonset diabetes of the young (MODY: MODY1, MODY2, MODY3, MODY4, MODY5,MODY6, MODY7, MODY8, MODY9, MODY10, MODY11)), Schizophrenia (Paranoidschizophrenia, Disorganized schizophrenia, Catatonic schizophrenia,Residual schizophrenia, Schizoaffective disorder), Myasthenia gravis(MG) (ocular myasthenia gravis, Congenital MG and generalized myastheniagravis), rheumatoid arthritis (RA), Graves' disease, Guillain-Barrésyndrome (GBS), Muscular Dystrophy (Duchenne Muscular Dystrophy (DMD)),Becker, Myotonic, Congenital, Emery-Dreifuss, Facioscapulohumeral,Limb-girdle, Distal, and Oculopharyngeal), severe burns, aging,Amyotrophic Lateral Sclerosis (ALS), Ataxia (Friedreich's Ataxia,Spinocerebellar ataxias 1 (SCA1), Spinocerebellar ataxias 2 (SCA2),Spinocerebellar ataxias 3 (SCA3), Spinocerebellar ataxias 6 (SCA6),Spinocerebellar ataxias 7 (SCAT), Spinocerebellar ataxias 11 (SCA11),Dentatorubral pallidolusyian atrophy (DRPLA) and Gluten ataxia), BattenDisease or neuronal ceroid lipofuscinoses (NCL) (infantile NCL (INCL),late infantile NCL (LINCL), juvenile NCL (JNCL) or adult NCL (ANCL)),Alzheimer's Disease (Early-onset Alzheimer's, Late-onset Alzheimer's,and Familial Alzheimer's disease (FAD)), Optic neuritis (ON), Leber'shereditary optic neuropathy (LHON), Autism Spectrum Disorders (ASD)(Asperger's Syndrome, Pervasive Developmental Disorders (PDDs),Childhood Disintegrative Disorder (CDD), and Autistic disorder), Rettsyndrome, Angelman's Syndrome, Leigh disease, Prader Willi Syndrome,Fragile-X Syndrome, Depression (Major Depression, Dysthymia, PostpartumDepression, Seasonal Affective Disorder, Atypical Depression, PsychoticDepression, Bipolar Disorder, Premenstrual Dysphoric Disorder,Situational Depression), Parkinson's disease (Idiopathic Parkinson'sdisease, Vascular parkinsonism, Dementia with Lewy bodies, InheritedParkinson's, Drug-induced Parkinsonism, Juvenile Parkinson's andatypical parkinsonism), mitochondrial diseases, developmental disorders,metabolic syndrome (increased blood pressure, high blood sugar level,excess body fat around the waist and abnormal cholesterol levels) and/orautoimmune disorders.

The dose may be administered as a single daily dose, a twice-daily dose,three times daily, or more frequently. The dose may be administeredthree times weekly, twice weekly, once weekly, or less frequently. In anembodiment, administration frequency may be between 1 and 5 times a day.In another embodiment, administration frequency may be between 2 and 4times a day. In another embodiment, administration frequency may be atleast 3 times a day. In another embodiment, administration frequency maybe twice a day. In another embodiment, administration frequency may beonce a day. In another embodiment, administration frequency may be lessfrequent than once a day. In other embodiments, administration frequencymay be once every 2 days or once every 3 days or once every 4 days oronce every 5 days or once every 6 days. In another embodiment,administration frequency may be once a week. In another embodiment,administration frequency may change with time, starting at a certainrate, such as once or twice a day, and then decreasing to lessfrequently, such as once every 2 days or once every 3 days, or once aweek, after the first day of treatment. In another embodiment,administration frequency may change with time, starting at a certainrate, such as once or twice a day, and then decreasing to lessfrequently, such as once every 2 days or once every 3 days, or once aweek, after the first two or three days of treatment. In anotherembodiment, administration frequency may change with time, starting at acertain rate, such as once or twice a day, and then decreasing to lessfrequently, such as once every 2 days or once every 3 days, or once aweek, after the first week of treatment. In another embodiment,administration frequency may be on demand, as therapeutic treatment isrequired or desired.

Since the study in the EAE model for MS showed that after 2 weeks of DNPtreatment, there is a statistically elevated level of BDNF protein3-weeks post treatment (FIG. 2b ), dose frequency could be chronic toraise BDNF protein levels, followed by infrequent doses or “drugholidays”. Infrequent doses would be used as maintenance doses to keepBDNF at elevated levels. Therefore, after an initial period of higherfrequency doses, frequency of doses could then be reduced to once everyweek, once every two weeks, once every three weeks or once a month.

It will be understood, based on the disclosure encompassed herein, howto determine whether a subject needs an additional and/or continueddose. It will also be understood that the selected dosing frequency mayrequire an adjustment of the dosage of active ingredient. It will alsobe understood, based on the disclosure encompassed herein, that theselected dosage of active ingredient may require an adjustment of thedosing frequency. The disclosure encompassed herein, in combination withthe skill in the art, will enable the skilled artisan to optimize boththe dosage of the active ingredient and the frequency of administrationof the active ingredient to treat a subject in need thereof.

The unit dose may also be adjusted based upon the size of the patient.The numbers provided herein are based upon a 60 kg patient. The sametherapy could be provided for a smaller or larger sized patient, butreducing or increasing the dose size. By way of example only, a 20 kgchild would need a much smaller dose.

Co-Administration of Compositions

In an embodiment, a composition described herein is administered inconjunction with one or more other medications or consumer products.Such other medications or consumer products may be administered orco-administered in forms and dosages as known in the art, or in thealternative, as has been described above for administration of activeingredients using the compositions described herein. By way of exampleonly, for stroke patients, DNP may be administered along with Tissueplasminogen activator (tPA).

For Diabetes Mellitus, DNP may be administered along with insulin(Humulin N, Novolin N) or other biologics as an injectable, or as anoral tablet with Metformin (Glucophage, Glumetza, others), sulfonylureas(glyburide (DiaBeta, Glynase), glipizide (Glucotrol) and glimepiride(Amaryl), etc.), Meglitinides (epaglinide (Prandin) and nateglinide(Starlix)), Thiazolidinediones (Rosiglitazone (Avandia) and pioglitazone(Actos)), DPP-4 inhibitors (sitagliptin (Januvia), saxagliptin (Onglyza)and linagliptin (Tradjenta)), GLP-1 receptor agonists ((Byetta) andliraglutide (Victoza)), SGLT2 inhibitors (canagliflozin (Invokana)and/or dapagliflozin (Farxiga)).

For Huntington's Disease, DNP may be administered with Tetrabenazine(Xenazine), Antipsychotic drugs, such as haloperidol (Haldol), or otherslike amantadine, levetiracetam (Keppra) and/or clonazepam (Klonopin).

For Parkinson's Disease, DNP may be administered with Carbidopa-levodopa(Rytary, Sinemet), Dopamine agonists such as pramipexole (Mirapex),ropinirole (Requip) and rotigotine (given as a patch, Neupro), ashort-acting injectable dopamine agonist, apomorphine (Apokyn), MAO-Binhibitors (Eldepryl, Zelapar), or Catechol-O-methyltransferase (COMT)inhibitors (Entacapone (Comtan), Tolcapone (Tasmar), etc.),Anticholinergics (benztropine (Cogentin), trihexyphenidyl), and/orAmantadine.

For Alzheimer's Disease, DNP may be administered with Cholinesteraseinhibitors (donepezil (Aricept), galantamine (Razadyne) and rivastigmine(Exelon)), and/or Memantine (Namenda).

For Depression, DNP may be administered with selective serotoninreuptake inhibitors (SSRIs) (luoxetine (Prozac), paroxetine (Paxil,Pexeva), sertraline (Zoloft), citalopram (Celexa) and escitalopram(Lexapro)), Norepinephrine-dopamine reuptake inhibitors (NDRIs).Bupropion (Wellbutrin, Aplenzin, Forfivo XL), atypical antidepressants(Trazodone, mirtazapine (Remeron), vortioxetine (Brintellix), vilazodone(Viibryd), etc.), and/or tricyclic antidepressants (imipramine(Tofranil), nortriptyline (Pamelor), Monoamine oxidase inhibitors(MAOIs) tranylcypromine (Parnate), phenelzine (Nardil), isocarboxazid(Marplan), etc.).

For Schizophrenia, DNP may also be administered along with Atypicalantipsychotics (Aripiprazole (Abilify), Asenapine (Saphris), Clozapine(Clozaril), Iloperidone (Fanapt), etc.), Conventional, or typical,and/or antipsychotics (Chlorpromazine, Fluphenazine, Haloperidol(Haldol), Perphenazine, etc.).

For MS, DNP may be administered along with Corticosteroids (prednisone,intravenous methylprednisolone), Beta interferons, Glatiramer acetate(Copaxone), Dimethyl fumarate (Tecfidera), Fingolimod (Gilenya),Teriflunomide (Aubagio), Natalizumab (Tysabri), Alemtuzumab (Lemtrada),and/or Mitoxantrone, etc.

For epilepsy, DNP may be administered along with Carbamazepine,clobazam, clonazepam, eslicarbazepine, ethosuximide, gabapentin,lacosamide, lamotrigine, levetiracetam, oxcarbazepine, perampanel,phenobarbital, phenytoin, pregabalin, primidone, retigabine, rufinamide,sodium valproate, tiagabine, topiramate, vigabatrin, and/or zonisamide,etc.

For Traumatic Brain Injury (TBI), DNP may be administered along withDiuretics, anti-seizure drugs, and/or Coma-inducing drugs.

For Lupus, DNP may be administered along with Nonsteroidalanti-inflammatory drugs (NSAIDs) (naproxen sodium (Aleve) and ibuprofen(Advil, Motrin IB, others)), Antimalarial drugs such ashydroxychloroquine (Plaquenil), Corticosteroids (Prednisone, etc.),and/or Immunosuppressants (azathioprine (Imuran, Azasan), mycophenolate(CellCept), leflunomide (Arava), methotrexate (Trexall), etc.).

For Prader Willi Syndrome, DNP may be administered along with Humangrowth hormone (HGH), and/or sex hormone treatment (testosterone formales or estrogen and progesterone for females), etc.

For Graves' disease, DNP may be administered along with Anti-thyroidmedications (propylthiouracil and methimazole (Tapazole)), and/or Betablockers (Propranolol (Inderal), Atenolol (Tenormin), Metoprolol(Lopressor, Toprol-XL), Nadolol (Corgard)).

For Muscular Dystrophy, DNP may be administered along withCorticosteroids, such as prednisone and/or Heart medications, such asangiotensin-converting enzyme (ACE) inhibitors or beta blockers.

DNP may also be administered along with pain relief medication,vitamins, nutrition, hydration fluids, or other medication.

The term “co-administration” or “combination therapy” is used todescribe a therapy in which at least two compositions, which may includeone or more product compositions as described herein, are used to treat,address, or affect a skin condition or another disorder as describedherein at the same time. In an embodiment, at least two compositions ineffective amounts are used to treat, address, or affect a skin conditionor another disorder as described herein at the same time. In anotherembodiment, at least two active ingredients, the combination of whichcomprises an effective amount, are used to treat, address, or affect askin condition or another disorder as described herein at the same time.In an embodiment, the result of treatment with the at least twocompositions may be additive of the treatment results obtained usingeach composition separately, either directly additive, or additive to adegree lesser than the results obtained with the two compositionsseparately. In an embodiment, the result of treatment with the at leasttwo compositions may be synergistic, to varying degrees. In anembodiment, the result of treatment with the at least two compositionsmay be greater than the treatment results obtained using eachcomposition separately. In an aspect, the result of treatment for atleast two active ingredients is less than that obtained with the activeingredients separately, while the other active ingredients in thecomposition are about the same as the results of treatment obtainedseparately. In an aspect, the result of treatment for all activeingredients in the composition is less than that obtained with theactive ingredients separately.

Although the term co-administration encompasses the administration oftwo compositions to the patient at the same time, it is not necessarythat the compositions be administered to the patient at the same time,although effective amounts of the individual active ingredientsdelivered by the compositions will be present in the patient at the sametime.

A product composition described herein may advantageously beadministered in combination with at least one other therapeutic agent toprovide improved treatment of a skin condition or another disorder. Thecombinations, uses and methods of treatment of the invention may alsoprovide advantages in treatment of patients or consumers who fail torespond adequately to other known treatments. In an embodiment, aproduct composition described herein may be administered to a patientalready undergoing treatment with at least one other skin carecomposition, to provide improved treatment of any combination ofconditions described herein. In an embodiment, a product composition setforth herein is co-administered with one or more lotions, foams, orcreams.

It will further be understood by the skilled artisan that, in additionto the above embodiments of dosage and dosing regimens, both the dosageand the dosing regimen will be considered and each adjusted, asnecessary, in view of the condition of the subject being treated.

It will be appreciated by those skilled in the art that changes could bemade to the exemplary embodiments shown and described above withoutdeparting from the broad inventive concepts thereof. It is understood,therefore, that this invention is not limited to the exemplaryembodiments shown and described, but it is intended to covermodifications within the spirit and scope of the present invention asdefined by the claims. For example, specific features of the exemplaryembodiments may or may not be part of the claimed invention and variousfeatures of the disclosed embodiments may be combined.

Unless specifically set forth herein, the terms “a”, “an” and “the” arenot limited to one element but instead should be read as meaning “atleast one”.

It is to be understood that at least some of the figures anddescriptions of the invention have been simplified to focus on elementsthat are relevant for a clear understanding of the invention, whileeliminating, for purposes of clarity, other elements that those ofordinary skill in the art will appreciate may also comprise a portion ofthe invention. However, because such elements are well known in the art,and because they do not necessarily facilitate a better understanding ofthe invention, a description of such elements is not provided herein.

Further, to the extent that the methods of the present invention do notrely on the particular order of steps set forth herein, the particularorder of the steps should not be construed as limitation on the claims.Any claims directed to the methods of the present invention should notbe limited to the performance of their steps in the order written, andone skilled in the art can readily appreciate that the steps may bevaried and still remain within the spirit and scope of the presentinvention.

1-60. (canceled)
 61. A pharmaceutical composition of 2,4-dinitrophenol(DNP), or a pharmaceutically acceptable salt, solvate, or hydratethereof, comprising an effective dose of 2,4-dinitrophenol (DNP) fortreating a neuromuscular, autoimmune, neurodegenerative, developmental,or metabolic disease or disorder, or a traumatic central nervous system(CNS) injury, in a patient in need thereof, wherein the effective doseof the 2,4-dinitrophenol (DNP) is in a range of 0.01 mg/kg of bodyweight to 5 mg/kg of body weight, and wherein the composition comprisesan immediate release formulation, a controlled release formulation, or asustained release formulation.
 62. The pharmaceutical composition ofclaim 61, wherein the effective dose of 2,4-dinitrophenol (DNP) is inthe range of about 0.01 mg/kg of body weight to about 0.1 mg/kg of bodyweight.
 63. The pharmaceutical composition of claim 61, wherein theeffective dose of 2,4-dinitrophenol (DNP) is in the range of about 0.1mg/kg of body weight to about 1 mg/kg of body weight.
 64. Thepharmaceutical composition of claim 61, wherein the effective dose of2,4-dinitrophenol (DNP) is in the range of about 1 mg/kg of body weightto about 5 mg/kg of body weight.
 65. The pharmaceutical composition ofclaim 61, wherein the composition comprises an immediate releaseformulation.
 66. The pharmaceutical composition of claim 61, wherein thecomposition comprises a controlled release formulation.
 67. Thepharmaceutical composition of claim 61, wherein the compositioncomprises a sustained release formulation.
 68. The pharmaceuticalcomposition of claim 61, wherein the disease, disorder, or injury isselected from Parkinson's disease, multiple sclerosis (MS), and spinalcord injury.
 69. A pharmaceutical composition of 2,4-dinitrophenol(DNP), or a pharmaceutically acceptable salt, solvate, or hydratethereof, comprising an effective 2,4-dinitrophenol (DNP) unit dose fortreating a neuromuscular, autoimmune, neurodegenerative, developmental,or metabolic disease or disorder, or a traumatic central nervous system(CNS) injury, in a patient in need thereof, wherein the unit dose is inthe range of about 0.1 mg to about 300 mg; and wherein the compositioncomprises an immediate release formulation, a controlled releaseformulation, or a sustained release formulation.
 70. The pharmaceuticalcomposition of claim 69, wherein the unit dose is in the range of about0.1 mg to about 1 mg.
 71. The pharmaceutical composition of claim 69,wherein the unit dose is in the range of about 1 mg to about 5 mg. 72.The pharmaceutical composition of claim 69, wherein the unit dose is ina range selected from about 5 mg to about 10 mg, about 10 mg to about 15mg, about 15 mg to about 20 mg, about 20 mg to about 30 mg, about 30 mgto about 40 mg, and about 40 mg to about 50 mg.
 73. The pharmaceuticalcomposition of claim 69, wherein the unit dose is in the range fromabout 50 mg to about 100 mg.
 74. The pharmaceutical composition of claim69, wherein the unit dose is in the range from about 100 mg to about 200mg.
 75. The pharmaceutical composition of claim 69, wherein the unitdose is in the range from about 200 mg to about 300 mg.
 76. Thepharmaceutical composition of claim 69, wherein the compositioncomprises an immediate release formulation.
 77. The pharmaceuticalcomposition of claim 69, wherein the composition comprises a controlledrelease formulation.
 78. The pharmaceutical composition of claim 69,wherein the composition comprises a sustained release formulation. 79.The pharmaceutical composition of claim 69, wherein the disease,disorder, or injury is selected from Parkinson's disease, multiplesclerosis (MS), and spinal cord injury.